Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer

Tamer A Elwaie; Mostafa M A Aref; Hamed I Ali

doi:10.1039/d6ra03011d

. 2026 Jul 3;16(34):31815–31855. doi: 10.1039/d6ra03011d

Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer

Tamer A Elwaie ^a,^b,^c, Mostafa M A Aref ^a, Hamed I Ali ^a,^✉

PMCID: PMC13329861 PMID: 42405118

Abstract

Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating innovative therapeutic strategies to overcome drug resistance and tumor heterogeneity. Breast cancer is a heterogeneous disease in which dysregulated tyrosine kinase signaling drives proliferation, survival, metastasis, and resistance. Tyrosine kinase inhibitors (TKIs) are pivotal targeted agents in breast cancer therapy, owing to their ability to modulate critical signaling pathways implicated in cancer progression. This review summarizes medicinal-chemistry strategies for designing small-molecule TKIs, integrating binding-mode classifications with scaffold selection and structure-guided optimization. Representative advances include HER2-selective, dual-RTK approaches such as EGFR/VEGFR-2 and EGFR/HER2 designs that enhance activity and overcome resistance. Emerging strategies, such as lapatinib-based PROTACs, demonstrate effective EGFR/HER2 degradation and strong antiproliferative activity in HER2-driven models, and have expanded beyond the HER family to include targets such as c-MET, FGFR, BTK, FAK, SRC, and JAK, highlighting their potential against the aggressive triple-negative breast cancer subtype. Studies featuring reversible and irreversible inhibitors, multi-targeted ligands, and covalent kinase inhibitors targeting BC are presented. These efforts underscore the importance of integrating scaffolds from promising candidate and clinically approved drugs to advance next-generation kinase inhibitors targeting breast cancer subtypes, thereby overcoming challenges and improving structural optimization outcomes.

Overview of HER2⁺ and TNBC resistance mechanisms, highlighting 6-kinase domain alignment, the back-pocket hydrophobic interaction, and diverse ATP hinge binders for targeted therapy design in tyrosine kinases.

Introduction

Breast cancer (BC) is the most diagnosed cancer and the main cause of cancer deaths among women globally.¹ Approximately two million patients are diagnosed with BC, and more than 600 000 deaths occur each year.² In the United States, 310 720 new cases of female BC have been estimated, and 42 250 deaths were reported in 2024.³ Considerably, drug-resistant cancer cells are responsible for most breast cancer fatalities. For this reason, researchers are developing novel chemotherapeutic drugs and targeted therapy combinations to overcome cancer cell resistance.⁴ BC is a genetically and clinically heterogeneous disease with multiple subtypes. The classification of these subtypes has evolved over the years. The most accepted classification of breast cancer is from an immunohistochemical perspective, based on the expression of the hormone receptors and human epidermal growth factor (HER2).⁵ Consequently, the following subtypes of breast cancer are commonly recognized as hormone-dependent, HER2-positive, and triple-negative breast cancers⁶ [Fig. 1].

Hormone receptor-positive (HR⁺) BC, also referred to as luminal breast cancer, is a common subtype that relies on hormones like estrogen and progesterone for growth.⁷ The estrogen receptor ER is more frequently related to postmenopausal women.⁸ Targeting estrogen has been used for many years to inhibit the estrogen signaling pathway in women with estrogen-positive breast cancer.⁹ HR⁺ breast cancer is classified based on molecular profiling into two major subtypes: luminal A and B.¹⁰

According to data from the National Cancer Institute (NCI), almost 90% of patients with HER2⁺ breast cancer survived five years post-diagnosis. Specific HER-2 mutations or the emergence of treatment resistance can negatively impact survival rates.¹¹ HER-2 dysregulation activates downstream signaling pathways, including PI3K/AKT/mTOR and MAPK/ERK, which promote cell survival, proliferation, and metastasis.¹²

The discovery of HER2 as a highly sensitive therapeutic target was a breakthrough for treating highly aggressive HER2-positive BC, leading to the approval of the first HER2-targeted drug, the monoclonal antibody trastuzumab.¹³ Since the identification of HER-2 receptor amplification as an adverse prognostic factor in a special subtype of metastatic breast cancer, there has been a substantial improvement in the survival of these patients due to the development of anti-HER2 targeted therapies.^14,15 HER-2-targeting drugs can be classified into monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates.¹³

TNBC is defined by the absence of estrogen, progesterone, and HER2 protein expression and is often associated with an unfavorable prognosis.¹⁶ TNBCs are biologically aggressive, and although some reports suggest that TNBC patients have a reasonable response rate to the current standard of chemotherapy, the relapse rates are high.¹⁷ Metastatic triple-negative breast cancer (mTNBC) is an aggressive type of breast cancer with limited treatment options and a low response rate.¹⁸

Breast cancer mortality is highly driven by metastatic progression, with estimates suggesting that approximately 90% of breast cancer mortality is attributable to metastasis.^19,20 BC tumor heterogeneity drives diverse metastatic patterns and promotes resistance to systemic therapies.²¹ The tumor microenvironment and formation of pre-metastatic niches facilitate metastatic cell survival and outgrowth.²² A remarkable metastatic example of BC is brain metastasis, which remains especially difficult to treat due to the blood–brain barrier (BBB), which limits drug penetration.^23–25 CNS involvement is particularly challenging because brain metastases occur in approximately 10–15% of patients with stage IV-metastatic breast cancer overall, but the frequency is substantially higher in aggressive molecular subtypes, reaching approximately 25–46% in metastatic TNBC and 30–50% in metastatic HER2⁺ BC.^26,27

TKIs represent a vital systemic treatment strategy for HER2⁺ breast cancer brain metastases (BCBM), mainly because their small molecular size allows better BBB penetration than many antibody-based therapies.^28,29 As the small-molecule TKIs have properties commonly reflected by MW <400–450 Da, TPSA <70–90 Å², clog P of approximately 2–4, low HBD/HBA counts, and rotatable bonds ≤6–8.^23,30

A meta-analysis of 13 clinical trials involving 987 patients with HER2-positive breast cancer brain metastases (BCBM) demonstrated clinically meaningful intracranial activity of HER2-targeted TKIs, with a trend toward improved PFS compared with non-TKI regimens (HR = 0.64; 95% CI: 0.35–1.15).²⁸ Median PFS and OS were 7.9 and 12.3 months, respectively. TKI-capecitabine combinations showed superior outcomes, while tucatinib emerged as the most favorable TKI, significantly improving PFS and OS in the HER2CLIMB trial compared with earlier agents such as lapatinib and neratinib.²⁸

TNBC brain metastasis (TNBC-BM) is a highly aggressive clinical condition with poor prognosis, where CNS involvement occurs more frequently than in hormone receptor-positive breast cancer and is driven by both tumor-intrinsic and brain microenvironmental mechanisms.³¹ Liu et al. reported a study that revealed that anlotinib, a multi-TKI, showed encouraging intracranial activity and manageable toxicity in heavily pretreated TNBC patients with brain metastases, achieving a median CNS PFS of 7.2 months, median OS of 10.2 months, iORR of 31.0%, and iDCR of 86.2%, with no treatment-related deaths.³²

In this review, we focus on medicinal chemistry and drug discovery strategies for designing small-molecule tyrosine kinase inhibitors to overcome the challenges in developing anti-breast cancer TKIs. Emphasis is placed on how scaffold optimization, structure–activity relationship analysis, kinase inhibition, and mechanistic evaluation have contributed to the development of more effective targeted therapeutic candidates. Targeted breast cancer therapies are designed to interfere with specific molecular pathways that regulate tumor cell proliferation, survival, angiogenesis, invasion, and therapeutic resistance. Accordingly, this review includes studies published in the last 10 years that investigated small-molecule kinase inhibitors targeting BC-relevant pathways, including tyrosine kinases such as HER family kinases, VEGFR, MET, FGFR, PDGFR, SRC, FAK, JAK, BTK, and related signaling pathways, with in vitro and/or in vivo results.

Kinase inhibitors as targeted treatments for breast cancer

Protein kinases (PKs) have been implicated in mediating the activation of signaling cascades in response to both extracellular and intracellular stimuli, thereby regulating cell proliferation and survival.³³ The regulation of receptor tyrosine kinase (RTK) activity is essential, as aberrant signaling can lead to pathological conditions, including cancer.³³ Mutations or overexpression of RTKs can result in uncontrolled cell proliferation and survival, underscoring the importance of these receptors in maintaining cellular homeostasis.³⁴ Kinases catalyze the transfer of a phosphate group from ATP to specific amino acid residues in protein substrates, modulating their function and activity.³⁵ Growth factors often function as dimers, either as homodimers (two identical subunits) or heterodimers (two different subunits), to activate their respective receptors and initiate intracellular signaling pathways.³⁶ RTKs undergo dimerization after ligand binding, leading to autophosphorylation of specific tyrosine residues within their cytoplasmic domains.³⁷ The activation of these signaling proteins propagates the signal initiated by the growth factor, ultimately influencing gene expression and cellular behavior.³⁷ Epidermal Growth Factor (EGF) binds to its receptor (EGFR), and EGF induces receptor dimerization, which is essential for signal transduction.³⁸ These dimeric interactions are crucial for the activation of signaling cascades that regulate various cellular processes, including proliferation, differentiation, and survival.³⁹ Alterations in these kinases due to specific mutations or abnormal protein overexpression have been closely linked to cancer, and these inherent mechanisms may lead to resistance to such small molecules.^33,40 Consequently, the development of new target-kinase drugs is required to simultaneously improve anti-tumor efficacy and address resistance.⁴¹

Kinase inhibitors (KIs) are classified according to the activation state of the protein kinase target, including the nature of DFG-Asp (active in, inactive out), the C-α-helix (active in, inactive out), and the regulatory spine (active linear, inactive distorted).⁴² This classification in Fig. 2 includes several types, each interacting differently with the kinase's conformation: (1) type I binds to the active conformation of the kinase, where the aspartate-phenylalanine-glycine (DFG) motif is in the ‘DFG-in’ position.⁴³ They occupy the ATP-binding pocket, directly competing with ATP, and erlotinib and bosutinib are examples.^42–44 (2) Type 1½ (type I subtype) binds to the ATP binding region and extends into the back pocket (DFG-in conformation and C-α-helix out), and lapatinib is an example of this subtype.⁴⁴ (3) Type II targets the inactive conformation of kinases, specifically binding to the ‘DFG-out’ state.^43,45 They extend into an adjacent allosteric site next to the ATP-binding pocket, stabilizing the inactive form, and sorafenib and nilotinib are examples.^43,45,46 In contrast, the allosteric inhibitors bind to the cleft between the N-lobe and C-lobe adjacent to the ATP-binding site, and they are classified into three types, III, IV, and V, based on the location of the allosteric site relative to the ATP-binding pocket. (4) Type III inhibitors bind within the allosteric active site, distinct from the ATP-binding pocket.⁴⁷ PD184352 (CI-1040), a selective inhibitor of mitogen-activated protein kinase 1/2 (MAP2K1/2, MEK1/2), was the first type III inhibitor to enter clinical trials, laying the foundation for the identification of additional non-ATP-competitive inhibitors.⁴⁸ (5) Type IV inhibitors are allosteric inhibitors that target regions external to the ATP-binding sites without overlapping with type III inhibitors.⁴⁹ Examples of FDA-approved type IV inhibitors are everolimus and temsirolimus.⁵⁰ (6) Type V (bivalent) inhibitors are molecules capable of interacting with two distinct regions of the protein kinase domain.⁵¹ (7) Type VI inhibitors are covalent interacting compounds that irreversibly block the target enzyme.⁵¹ The irreversible covalent bonds with specific amino acid residues (often cysteine) within the kinase lead to permanent inhibition.⁵²

Tyrosine kinases are broadly classified into two main categories: receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs).⁵³ Receptor tyrosine kinases (RTKs) are essential receptors that initiate and advance multifactorial breast cancer, resulting from acquired genetic and epigenetic modifications that impair cellular signaling pathways.⁵⁴ RTKs have an external ligand-binding domain, a solitary transmembrane helix, and an intracellular tyrosine kinase domain.³⁴ Upon ligand interaction, receptor tyrosine kinases (RTKs) generally undergo dimerization, resulting in the autophosphorylation of tyrosine residues in their cytoplasmic domains.⁵⁵ This autophosphorylation increases their kinase activity and establishes docking sites for downstream signaling molecules, thereby activating numerous intracellular signaling pathways.³⁷ Examples of RTKs include the Epidermal Growth Factor Receptor (EGFR), which is implicated in cellular growth and differentiation. Platelet-derived growth factor receptor (PDGFR) is involved in embryonic development and tissue repair.⁵⁶ Fibroblast Growth Factor Receptor (FGFR) is implicated in the development of limbs and the neurological system.⁵⁶ The Vascular Endothelial Growth Factor Receptor (VEGFR) is essential for angiogenesis, metastasis, and resistance.^57,58

Despite their clinical value, KIs also pose challenges, including the development of resistance and potential side effects such as cardiotoxicity and gastrointestinal complications.^59–61 Current KIs are associated with several toxicity and off-target challenges that can limit dose intensity, long-term tolerability, and therapeutic selectivity.^62–65 Major safety concerns include on-target toxicity in normal tissues where the inhibited kinase performs essential physiological functions, as well as off-target inhibition of structurally related kinases due to the conserved nature of the ATP-binding site, which may result in cardiotoxicity, gastrointestinal toxicity, dermatologic adverse effects, hepatotoxicity, and broader toxicity resulting from excessive or poorly selective multi-kinase inhibition.^62,66–69

The structural basis indicates that most kinase inhibitors are ATP-competitive, with selectivity enhanced by targeting differences in residues that line the ATP-binding site, adjacent inactive-state pockets, and allosteric sites.⁷⁰ Modifying the hinge-binding group is a structural optimization strategy because many kinase inhibitors form key hydrogen bonds with hinge-region residues.^70,71 Kinase selectivity profiling is a standard method for detecting off-target kinase interactions during inhibitor development.^72,73 For covalent inhibitors, recent research highlights the importance of electrophile or warhead design and reactivity regulation to minimize unintended covalent reactions while maintaining efficacy.^74,75 PROTAC-based kinase degradation is gaining recognition as a strategy for more sustained target suppression and, in some cases, to address limitations associated with occupancy-dependent kinase inhibition.^76,77

The review discusses selective, dual-, and multitargeting approaches as complementary design strategies, with selective inhibitors used to strengthen the rationale for targeting breast cancer subtypes in drug design.^78,79 Selective inhibition is most appropriate when breast cancer is driven by a dominant validated kinase, such as HER2, where improved selectivity may reduce off-target toxicity and improve safety.^80,81 On the other hand, dual- or multitarget inhibition is more relevant for heterogeneous, metastatic, or resistant breast cancer, particularly TNBC or therapy-resistant HER2-positive disease, where compensatory signaling pathways may limit the efficacy of single-target inhibition.⁸²

Resistance mechanisms in kinase-targeted therapies in breast cancer treatment

The resistance mechanisms in kinase-targeted therapies arise from molecular changes within the inhibited kinase itself that reduce drug binding or restore kinase activity despite treatment.^83,84 These alterations may include gatekeeper mutations, ATP-binding-site mutations, activation-loop substitutions, kinase-domain amplification or overexpression, and conformational changes that stabilize the active kinase state.^43,84

HER-2-acquired resistance is common and reduces the effectiveness of clinical responses.⁸⁵ The HER2 T798 M mutation, a gatekeeper mutation in ErbB2 exon 20, produces a kinase mutant with constitutive phosphorylation and activation.⁸⁶ The impeding effect reduces the affinity of wild-type-selective inhibitors, while additional nonbonded contacts increase the affinity of wild-type-sparing inhibitors, resulting in mutant selectivity.⁸⁷ HER2-V777L mutation, an intrinsic activating mutation, leads to a valine-to-leucine substitution at codon 777 within the HER2 kinase domain (HER2 V777L).⁸⁸ HER-2 L755 mutations, which include modifications in the kinase domain, restore HER2 signaling in HER2-positive breast cancer models, resulting in resistance to potent anti-HER2 therapies.⁸⁹ Administering irreversible HER1/2 inhibitors to HER2⁺ breast cancer patients with activating lapatinib-resistant mutations, such as the L755S mutation, may improve their clinical results.⁹⁰ L755P and L755S are oncogenic HER-2 variants, with L755P often associated with greater kinase activation and therapeutic resistance.⁹¹

Bypass and compensatory signaling are major resistance mechanisms in heterogeneous breast tumors, TNBC, metastatic disease, and therapy-resistant HER2-positive breast cancer.^92,93 Cancer cells can survive primary kinase inhibition by activating alternative receptor tyrosine kinases or downstream pathways, including EGFR, HER3, MET, FGFR, IGF1R, VEGFR, SRC/FAK, JAK/STAT, PI3K/AKT/mTOR, and MAPK signaling.^82,94,95 Kinase inhibition may also relieve negative feedback loops, thereby promoting adaptive kinome reprogramming and reducing tumor-cell dependence on the original target.^96–98 This adaptive response has been observed in breast cancer models, in which targeted MEK or HER2 inhibition can induce compensatory activation or transcriptional upregulation of multiple receptor tyrosine kinases and downstream signaling nodes.^96,97

Pharmacologic resistance arises when drug exposure at the tumor site is insufficient, without direct alteration of the kinase target.^99,100 This can result from poor absorption, rapid metabolism, altered tissue distribution, limited tumor penetration, or increased efflux by ATP-binding cassette transporters.^99,100 Tumor cells may also evade kinase inhibition through phenotypic plasticity, including epithelial–mesenchymal transition, stem-like or drug-tolerant persister states, altered differentiation, enhanced invasion, and metastatic adaptation.^101–104

The tumor microenvironment can further promote resistance through protective signals from stromal cells, immune cells, extracellular matrix components, hypoxia, angiogenic factors, cytokines, and growth factors.^105,106 In metastatic and angiogenesis-driven breast cancer, VEGF/VEGFR, integrin/FAK, SRC, inflammatory signaling, and growth factors crosstalk may sustain tumor survival despite kinase inhibition.^107–109

Major kinase-targeted therapeutic strategies in breast cancer

In breast cancer, the selection of a kinase-targeted strategy should be guided by tumor subtype, oncogenic driver dependence, pathway redundancy, resistance mechanisms, and pharmacokinetic suitability.^110–113 Therefore, as summarized in Table 1, kinase inhibitor classes should be compared not only on the basis of potency but also on their target-binding mode, kinase selectivity, potential to overcome resistance, safety profile, and therapeutic relevance in breast cancer.^{46,70,114,115}

Table 1. Comparative overview of major kinase-targeted therapeutic strategies in breast cancer, highlighting their mechanisms, advantages, limitations, and context-dependent applications across selective, covalent, multitarget, hybrid, degrader-based, and combination approaches.

Inhibitor class	Mechanism	Key advantages	Main limitations	Best use in breast cancer	References
Reversible ATP-competitive TKIs	Noncovalent binding to the ATP site; commonly type I or type II	Tunable potency/selectivity; controllable target blockade; lower risk of permanent off-target modification	Transient inhibition; vulnerable to ATP-site mutations, gatekeeper mutations, and bypass signaling	Driver-dependent tumors where selective kinase inhibition is sufficient, such as HER2⁺ disease	46, 114, 116 and 117
Irreversible/covalent TKIs	Covalent binding to a reactive residue near the kinase active site	Sustained inhibition; prolonged target engagement; may overcome selected resistant mutants	Off-target covalent reactivity; toxicity risk; requires specific optimization for the irreversible groups	Mutation-driven or persistent kinase signaling, including selected EGFR/HER2 resistance	118–120
Allosteric inhibitors	Bind outside the ATP pocket, including type III/IV sites	Higher selectivity potential; may overcome ATP-site resistance; less competition with ATP	Fewer validated pockets; target-specific design challenges; limited BC-specific examples	When ATP-site conservation limits selectivity, or ATP-site mutations reduce activity	46, 47, 114 and 121
Multi-target TKIs	Inhibit two or more kinases/pathways	Blocks compensatory signaling; may reduce adaptive resistance	Greater off-target risk; complex SAR and safety optimization	Heterogeneous, metastatic, TNBC, or resistant HER2-positive tumors with pathway redundancy	61, 92 and 137
Hybrid inhibitors	Single molecule combining two pharmacophores, such as kinase/HDAC or kinase/PARP	Integrates complementary mechanisms; may address crosstalk or resistance	Larger structures; harder to optimize potency, selectivity, solubility, and permeability	Tumors requiring simultaneous kinase plus epigenetic or DNA-repair targeting	123–126
PROTACs/kinase degraders	E3 ligase recruitment induces proteasomal degradation of the kinase protein	Removes whole protein; prolonged suppression; may overcome scaffold-function or binding-site resistance	High molecular weight; permeability, PK, linker, and E3-ligase dependence	Resistant tumors where kinase degradation may outperform catalytic inhibition alone, such as EGFR/HER2 degrader strategies	127–129
Combination-based kinase targeting	Uses separate agents to inhibit parallel pathways	Flexible dosing; avoids forcing all activities into one molecule; useful for bypass signaling	Drug–drug interactions; toxicity; schedule and dose complexity	HER2-resistant disease, TNBC, or metastatic tumors with adaptive pathway activation	130, 132 and 134–136

Open in a new tab

Reversible ATP-competitive TKIs are a foundational class of kinase inhibitors.¹¹⁴ They bind noncovalently to the ATP-binding site and provide tunable inhibition of kinase activity.^46,114 This approach is most suitable when breast cancer is driven by a validated oncogenic kinase, such as HER2, and selective target blockade is sufficient.¹¹⁶ The limitations of reversible inhibitors may include loss of activity due to ATP-site or gatekeeper mutations, high intracellular ATP levels, or compensatory pathway activation.^114,116,117

Irreversible or covalent TKIs provide more prolonged target inhibition by forming a covalent bond with a reactive residue near the kinase active site.¹¹⁸ This may be advantageous in tumors with persistent EGFR/HER2 signaling or in tumors with selected resistance mutations.^118,119 Nevertheless, covalent inhibitors require careful warhead optimization to maintain selectivity and minimize off-target reactivity.^118,120

Allosteric inhibitors bind outside the conserved ATP-binding pocket and may offer improved selectivity because allosteric sites are generally less conserved.^47,114,121 They may also retain activity when ATP-site alterations reduce the efficacy of ATP-competitive inhibitors.^47,121 However, their broader application in breast cancer remains limited by the availability of validated, druggable allosteric pockets.^47,114

Multi-target TKIs inhibit more than one kinase or signaling pathway within a single molecule.⁷⁸ This strategy is particularly relevant in heterogeneous, metastatic, TNBC, or therapy-resistant HER2-positive breast cancers, where compensatory signaling through EGFR, HER3, MET, FGFR, VEGFR, SRC/FAK, JAK/STAT, PI3K/AKT, or MAPK pathways can limit single-target inhibition.^78,79,122 Their main advantage is simultaneous blockade of pathway redundancy, but broader kinase inhibition may increase off-target toxicity and complicate SAR optimization.^111,114

Hybrid inhibitors combine two pharmacophores within one molecule, such as kinase/HDAC or kinase/PARP hybrids.^123,124 These agents may be useful when kinase signaling intersects with epigenetic regulation, DNA repair, or other resistance-associated mechanisms.^123–125 Still, the drawbacks of their application are that larger, more complex structures can make it more challenging to optimize potency, selectivity, solubility, permeability, and safety.^125,126

PROTACs and kinase degraders remove the kinase protein through E3 ligase-mediated proteasomal degradation rather than only inhibiting catalytic activity.^127,128 This strategy may provide prolonged pathway suppression and may be useful when resistance is driven by kinase overexpression, scaffold functions, or mutations that reduce inhibitor binding.^127,128 In EGFR/HER2-driven breast cancer, degrader-based approaches may be valuable in resistant BC subtypes, although their development is limited by high molecular weight, permeability barriers, pharmacokinetic liabilities, linker dependence, and E3 ligase expression.^60,127–129

Combination-based kinase targeting uses separate agents to inhibit parallel or compensatory pathways.¹³⁰ This approach offers dosing flexibility and may be useful in HER2-resistant disease, TNBC, or metastatic tumors with adaptive pathway activation.^131–133 The major drawbacks and limitations are considered, as it requires cautious management of overlapping toxicity, drug–drug interactions, dosing schedule, and patient selection.^{130,132,134–136}

Toxicity and off-target challenges of breast cancer TKIs

Toxicity and off-target effects remain central limitations in the development of TKIs for breast cancer.^61,63 Toxicities may arise from on-target effects, caused by excessive inhibition of the intended tyrosine kinase, and/or from off-target effects, resulting from unintended inhibition of additional kinases due to limited selectivity.^61,78,138

For HER-family inhibitors, one of the most clinically relevant toxicities results from EGFR inhibition in normal epithelial tissues, not strictly an off-target effect; rather, it reflects on-target inhibition of wild-type EGFR in tissues that depend on EGFR signaling for normal epithelial maintenance and repair, particularly the skin and gastrointestinal tract, leading to skin toxicities and diarrhea.^139,140 Skin adverse reactions have been reported in up to 90% of patients receiving EGFR inhibitors, ranging from common toxicities such as papulopustular rash, paronychia, and hair alterations to rare but severe events, including Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.^139,141 HER2-selective inhibition, as exemplified by tucatinib, was designed to retain HER2 blockade while minimizing EGFR inhibition.¹⁴² The development of a selective HER2 inhibitor is important because HER2⁺ breast cancer benefits from selective HER2 inhibition when HER2 is the dominant oncogenic driver, whereas unnecessary EGFR inhibition can reduce tolerability.¹⁴²

HER-family TKIs, particularly HER2-directed agents such as lapatinib and tucatinib, can be associated with clinically relevant hepatotoxicity.^143,144 Lapatinib is metabolized primarily by CYP3A4 and CYP3A5, and liver injury may result from toxic or immunogenic intermediates.¹⁴⁵ Towles et al. specifically examined CYP3A4- and CYP3A5-mediated lapatinib bioactivation leading to a reactive, potentially toxic lapatinib quinone-imine metabolite, LAPQI.¹⁴⁵ Hardy et al. further showed that CYP3A4 induction can potentiate lapatinib hepatotoxicity through increased reactive metabolite formation.¹⁴⁶

Structural optimization of HER2 inhibitors can reduce associated hepatotoxicity by improving kinase selectivity, minimizing BSEP inhibition, reducing excessive lipophilicity, and replacing metabolic moieties.^147–151 Selective scaffolds such as tucatinib may reduce off-target kinase and transporter liabilities, while lipophilicity control can limit hepatic accumulation and reactive metabolite formation.^150–152 Moreover, deuterium substitution is a promising approach to slow oxidative bioactivation and mitigate key structural drivers of drug-induced liver injury.^152,153

Multikinase inhibitors have broader off-target kinase inhibition, which remains a central concern because conservation of the ATP-binding site can lead to unintended inhibition of kinases required for normal tissue homeostasis.¹⁵⁴ This may contribute to cardiovascular, vascular, renal, hepatic, and epithelial toxicities.^154–156

Medicinal chemistry can mitigate the off-target toxicity and kinase-conservation limitations of type I multikinase inhibitors through several complementary design strategies: first, allosteric inhibitors, including type III, IV, and V kinase inhibitors, avoid direct competition with ATP by targeting less conserved regulatory pockets, thereby improving selectivity and reducing unintended kinase inhibition.^47,157,158 Second, type II inhibitors exploit inactive kinase conformations, such as the DFG-out state, and access adjacent hydrophobic pockets or gatekeeper-dependent regions that differ across kinases, enabling more selective target engagement.^159,160 Third, reversible covalent inhibitors use attenuated electrophilic warheads, such as optimized cyanoacrylamides, to transiently interact with non-catalytic cysteine residues that are unique or rare in the target kinase, combining prolonged residence time with improved safety compared with irreversible covalent binding.^161,162 Finally, targeted protein degradation approaches, such as PROTACs, shift the strategy from occupancy-driven inhibition to event-driven kinase degradation, in which selectivity depends on productive ternary complex formation among the kinase, degrader, and E3 ligase.^163,164 These approaches provide structurally guided routes to overcome ATP-site conservation, reduce multikinase off-target activity, and improve the therapeutic window of kinase-targeted therapies.

Human epidermal growth factor receptors

In cancer, ligand binding activates EGFR signaling, which forms homodimers or heterodimers with other EGFR family members and phosphorylates EGFR, thereby activating PI3K/AKT,¹⁶⁵ RAS/RAF/MEK/MAPK,¹⁶⁶ and JAK/STAT.¹⁶⁷ These pathways regulate cell growth, differentiation, motility, apoptosis, invasion, migration, adhesion, and angiogenesis.¹⁶⁸

As listed in Table 2, pan-HER inhibitors are of considerable interest in breast cancer therapy, as exemplified by a series of rationally designed, synthesized, and evaluated quinazolin-4-amine derivatives. Among them, compound 1, bearing an N-(3-bromo-1H-indol-5-yl)quinazolin-4-amine core, exhibited an irreversible mode of binding comparable to established pan-HER inhibitors. Compound 1 demonstrated very high inhibitory activities against EGFR and HER2-expressing cells, SK-BR-3 and BT-474, with potency across the HER family, inhibiting EGFR (IC₅₀ = 0.38 nM), HER2 (IC₅₀ = 3.5 nM), and HER4 (IC₅₀ = 1.6 nM). It also demonstrated potent inhibition of the T790M/L858R mutant EGFR (IC₅₀ = 2.2 nM).¹⁶⁹

Table 2. EGFR inhibitors with the reported anti-breast cancer activity.

Compound	Targets	Activity against BC cells	EGFR inhibition	References
1	Pan-HER	Strongly inhibited the cells that are EGFR and HER2 expressive, (SK-BR-3 and BT-474) more potent than afatinib	EGFR WT (IC₅₀ = 0.38 nM) and T790M/L858R	169
			(IC₅₀ = 2.2 nM) compared to afatinib EGFR WT (IC₅₀ = 0.67 nM) and T790M/L858R
			(IC₅₀ = 3.7 nM)
2	EGFR	MCF-7 (IC₅₀ = 8.91 µM) compared to lapatinib (IC₅₀ = 9.71 µM)	EGFR (66% @ 10 µM)	170
3	EGFR	MCF-7 IC₅₀ = 5.97 µM	IC₅₀ = 0.16 µM	171
3	EGFR	Gefitinib (IC₅₀ = 4.17 µM)	Gefitinib (IC₅₀ = 0.04 µM)	171
4	EGFR and ARO	MCF-7 IC₅₀ = 8.15 µM	Dual EGFR and ARO inhibitory activity with IC₅₀ of 0.045 and 0.146 µM, respectively	172
		Erlotinib (IC₅₀ = 18.0 µM)	Erlotinib EGFR IC₅₀ = 0.045 µM, letrozole ARO IC₅₀ = 0.043 µM
		Letrozole (IC₅₀ = 9.56 µM)
5	EGFR and PARP	HCC1937 IC₅₀ = 3.23 µM	EGFR % inhibition is comparable to afatinib at the concentration of 10 µM in HCC1937 cells	173
		Olaparib (>200 µM)
		MDA-MB-468 IC₅₀ = 15.6 µM
		Olaparib (200 µM)
		MX-1 IC₅₀ = 18.7 µM
		Olaparib (35.8 µM)
		SKBR3 IC₅₀ = 50 µM
		Olaparib (232 µM)

Open in a new tab

The pyrimidine compound 2 exhibited notable cytotoxicity against MCF-7 BC cells (IC₅₀ = 8.91 µM) while maintaining favorable selectivity over normal peripheral blood mononuclear cells (SI = 23.2). Compound 2 induced apoptosis in MCF-7 cells and significantly inhibited EGFR activity (66% inhibition at 10 µM).¹⁷⁰ Moreover, the pyrazoline compound 3 emerged as an EGFR-TK inhibitor (IC₅₀ = 0.16 µM, compared to gefitinib, 0.04 µM) and showed anti-breast cancer activity against MCF-7 cells (IC₅₀ = 5.97 µM).¹⁷¹

Sobh et al. reported a series of rationally designed, synthesized, and biologically evaluated benzothienopyrimidine scaffolds against the MCF-7 breast cancer cell line, using erlotinib and letrozole as reference standards. This scaffold yielded eight derivatives with up to 20-fold greater antiproliferative activity than erlotinib, and five compounds showed up to 11-fold higher potency than letrozole in the MTT assay. The most active candidates were subsequently assessed for their ability to inhibit EGFR and aromatase (ARO). Among them, compound 4 emerged as a potent dual inhibitor of both targets, with IC₅₀ values of 0.045 µM for EGFR and 0.146 µM for ARO.¹⁷²

A series of bicyclic tetrahydropyridine-pyrimidine scaffolds was developed by Lin et al. to overcome the limited response of RTK-overexpressing TNBC to classical PARP inhibitors. Promisingly, compounds were more potent than olaparib, particularly in TNBC. Compound 5 suppressed EGFR/p-EGFR expression and potently inhibited PARP activity, showing effective cytotoxicity against the breast cancer cells HCC1937 (IC₅₀ = 3.23 µM), MDA-MB-468 (15.6 µM), MX-1 (18.7 µM), and SKBR3 (50 µM), surpassing the olaparib activity.¹⁷³

HER-2 inhibition

HER2 (ErbB2) differs from the other ERBBs by its ligand-independent activation, tendency to heterodimerize, and strong association with cancer aggressiveness.⁸ HER2 is overexpressed in many cancers, contributing to aggressive progression, poor prognosis, and resistance to treatment.⁸¹ These features make HER2 a vital therapeutic target, distinguishing it from other ERBB family members that depend on ligand binding for activation.¹⁷⁴ HER2 inhibition primarily targets HER2⁺ breast cancer, offering strategies that significantly improve treatment outcomes and minimize side effects by specifically targeting the overexpressed HER2 receptors on cancer cells. These therapies suppress tumor growth and proliferation while sparing normal cells.¹⁷⁵

The example in Fig. 3 is the crystal structure of the HER2 kinase domain in complex with the inhibitor TAK-285 (PDB: 3RCD), which illustrates several key pockets within its catalytic cleft. The ATP-binding pocket, located between the N-terminal and C-terminal lobes of the kinase domain, binds the adenine portion of ATP. In the 3RCD co-crystal structure, TAK-285 (6) occupies this pocket, forming H-bonds with ATP hinge-region residues and effectively mimicking ATP to inhibit kinase activity. Adjacent to this is the hydrophobic back pocket, which accommodates hydrophobic inhibitor groups that stabilize specific inactive conformations. TAK-285 (6) extends into this hydrophobic region, interacting with non-polar residues to enhance binding affinity.¹⁷⁶ Tucatinib (7) is a selective, ATP-competitive small molecule tyrosine kinase inhibitor (TKI) that exhibits nanomolar potency against the HER2 receptor.¹⁷⁷ Tucatinib (7) effectively inhibits the phosphorylation of HER2 and its downstream effector, AKT3, in cell lines that overexpress HER2.¹⁷⁷

The preclinical efficacy of zongertinib (9) is evidenced by objective responses in patients with HER2-dependent malignancies, such as breast cancer (HER2 V777L mutation), thereby supporting its further clinical development.¹⁷⁸ The significance of the irreversible binding in the activity of zongertinib is noticed by the reduced potency observed with BI-3999 (8), an acetamide-matched pair compound of zongertinib that is unable to form a covalent bond with HER2, in which equivalent potency in Ba/F3 HER2^YVMA cells was observed to that measured for zongertinib (9), in the HER2^YVMA,C805S cell line.¹⁷⁸ The clinical study is evaluating the safety of zongertinib, given single or combined with established HER2 therapies, in patients with HER2⁺ metastatic breast cancer.¹⁷⁹

Yang et al. designed and prepared a series of dioxin-incorporating pyrazoline derivatives with a thiourea skeleton and evaluated their EGFR/HER-2 inhibitory activities. Most of the synthesized compounds exhibited selective HER-2 inhibitory activity. Compound 10 had the best selectivity score of 900, with HER2 IC₅₀ = 0.03 µM and EGFR IC₅₀ = 28.56 µM. Meanwhile, lapatinib demonstrated a selectivity score of 1, with HER2 & EGFR IC₅₀ values of 0.01 µM. In addition, compound 10 displayed promising antiproliferative activity against MDA-MB-453 breast cancer cell line.¹⁸⁰

Ibrahim et al. designed and synthesized a series of N-arylpyrimido[4,5-b]quinolines and 2-aryl-2,3-dihydropyrimido[4,5-b]quinoline-4(1H)-ones as potential anti-breast cancer agents. Several compounds demonstrated notable antiproliferative activity against MCF7 cells. Compound 11 emerged as the most potent candidate with an IC₅₀ of 1.67 µM. Mechanistic studies revealed that 11 induces apoptosis and arrests the cell cycle at the S phase. Consistent with the computational findings (PDB: 3PP0), it also exhibited strong HER2 inhibitory activity with an IC₅₀ of 0.073 µM, supporting HER2 as a probable molecular target underlying its antiproliferative effect.¹⁸¹

Mohamady et al. reported the green synthesis of 18 pyrazolopyridine derivatives and evaluated their anticancer activity across a panel of human tumor cell lines. From this set, compound 12 emerged as the most promising, exhibiting selective inhibition of HER2 (88%), comparable to that of the clinically used HER2 inhibitor tucatinib (90%). Apoptosis assays in HER2⁺ BT-474 cells confirmed their target-specific cytotoxicity. Moreover, compound 12 demonstrated notable in vivo efficacy in a breast cancer xenograft model, achieving a 19.45% reduction in tumor volume, approaching the effect of lapatinib (38.6%).¹⁸²

Reversible dual EGFR/HER-2 kinase inhibitors

Small-molecule tyrosine kinase inhibitors (TKIs) have potential advantages over monoclonal antibody therapies. These advantages include their oral bioavailability and their ability to inhibit multiple kinases and p95 HER2 (highly active truncated HER2 lacking most of the extracellular domain).^15,183 Likewise, TKIs have lower cardiopulmonary toxicities commonly associated with monoclonal antibody therapies^184,185 and a greater ability to penetrate the BBB, with greater therapeutic potential against brain metastases of metastatic breast cancer.¹⁸⁶

In 2020, Elwaie et al. reported the design and synthesis of 4,6-disubstituted quinazolines targeting HER2, with enhanced selectivity over the dual EGFR/HER2 inhibitor lapatinib. Selectivity was targeted to minimize EGFR-associated side effects of EGFR inhibitors. Interestingly, protein kinase profiling assay revealed compounds (13a,b, and 14) Fig. 4 as potent HER2 inhibitors with minimal or insignificant inhibition of the antitarget ABL1 (−25 to −40%) compared to lapatinib (−90% inhibition of ABL1).¹⁸⁷

Pouli group reported the design and synthesis of lapatinib analogs by replacing the hinge-binding quinazoline core with a purine isostere. The hydrophilic side chain of lapatinib was maintained to optimize the drug-like properties of the synthesized compounds.¹⁸⁸ The antiproliferative activity of the purine analogs (16) was evaluated against the HER2-overexpressing breast cancer cell line HCC1954. The isosteric modification of lapatinib didn't reveal any significant improvement in activity against the HCC1954 HER2⁺ breast cancer cell line¹⁸⁸ [Fig. 4].

Milik et al. designed and synthesized dual EGFR/HER2 inhibitors based on the quinazoline isosteric nucleus thieno[2,3-d]pyrimidine as a core scaffold and hinge binder. Their design proceeded by optimizing the balance between hydrophilic and lipophilic residues to achieve optimal enzymatic and cellular inhibitory activity. They finally identified compound 18 as a dual EGFR/HER2 inhibitor, with IC₅₀ values of 91.7 nM and 1.2 µM against EGFR and HER2, respectively. Compound 18 exhibited more potent antiproliferative activity in the HER-2-overexpressing breast cancer cell line MDA-MBA-361, with an IC₅₀ of 3.5 µM, compared to lapatinib, IC₅₀ = 13.73 µM [Fig. 4].¹⁸⁹

Li et al. prepared a series of 6-salicyl-4-anilinoquinazoline derivatives and evaluated their inhibitory activities against EGFR/HER2. In Fig. 4, among the synthesized derivatives, compound 19a demonstrated dual inhibitory activity (IC₅₀ values of 0.12 µM and 0.096 µM, respectively) and potent antiproliferative activity against the HER2-overexpressing MDAMB-453 BC cell line (IC₅₀ = 0.92 µM).¹⁹⁰ Although compound 19a doesn't bear a bulky aniline, it showed dual EGFR/HER2 inhibitory activities, which may be attributed to the contribution of the trifluoromethyl group. The explanation was confirmed by replacing the trifluoromethyl group with a chloro substituent, which led to a 30-fold decrease in HER2 inhibition and a 10-fold decrease in EGFR inhibition. Moreover, compound 19a showed 100-fold selectivity in a panel of 9 closely related kinases, and a computational study reported a different binding mode, with the 4-trifluoromethyl salicyl moiety directed toward the back pocket rather than the solvent-accessible region.¹⁹⁰

The structural comparison in Table 3 helps identify the pharmacophoric features of the dual EGFR/HER-2 inhibitors. Fakhry et al. designed and synthesized a series of thiazolyl-pyrazoline derivatives by combining thiazole and pyrazoline pharmacophores from pyrazoline carbothioamides as key precursors, with the aim of developing dual EGFR/HER2 inhibitors. Compound 20 exhibited the most potent cytotoxicity against MCF-7 cells, with an IC₅₀ of 3.54 µM, exceeding lapatinib (IC₅₀ = 5.88 µM). Enzymatic assays confirmed strong dual-kinase inhibition in the most active candidates. Notably, compound 20 demonstrated potent inhibition of EGFR (IC₅₀ = 5 nM) and HER2 (IC₅₀ = 22 nM) compared to lapatinib, with activity of EGFR (IC₅₀ = 7 nM) and HER-2 (IC₅₀ = 18 nM).¹⁹¹

Table 3. Anti-breast cancer EGFR/HER-2 dual inhibitors.

Compound	Targets	Activity against BC cells	EGFR/HER-2 inhibitions	References
20	EGFR, HER-2	MCF-7 IC₅₀ = 3.37 µM	EGFR (IC₅₀ = 5 nM)	191
		-Lapatinib	HER-2 (IC₅₀ = 22 nM)
		MCF-7 IC₅₀ = 5.88 µM	Lapatinib
			EGFR (IC₅₀ = 7 nM)
			HER-2 (IC₅₀ = 18 nM)
21a,b	EGFR, HER-2, BRAFV600E	MCF-7	(21a)	192
		21a (IC₅₀ = 27 nM)	- EGFR (IC₅₀ = 76 nM)
		21b (IC₅₀ = 24 nM)	- HER-2 (IC₅₀ = 33 nM)
		Erlotinib (IC₅₀ = 40 nM)	(21b)
			- EGFR (IC₅₀ = 71 nM)
			- HER-2 (IC₅₀ = 29 nM)
			Erlotinib
			- EGFR (IC₅₀ = 80 nM)
			Lapatinib
			- HER-2 (IC₅₀ = 26 nM)
22	EGFR, HER-2	SKBr3 (IC₅₀ = 6.971 µM)	EGFR (IC₅₀ = 90 nM)	193
		BT474 (IC₅₀ = 2.769 µM)	HER-2 (IC₅₀ = 80 nM)
		MDA-MB-453 (IC₅₀ = 11.472 µM)	Geftinib
		Lapatinib	EGFR (IC₅₀ = 40 nM)
		SKBr3 (IC₅₀ = 9.614 µM)	Lapatinib
		BT474 (IC₅₀ = 23.691 µM)	HER-2 (IC₅₀ = 110 nM)
		MDA-MB-453 (IC₅₀ = 29.762 µM)
23	EGFR, HER-2	MCF-7 IC₅₀ = 23 nM	EGFR (IC₅₀ = 71 nM)	194
		Erlotinib	HER-2 (IC₅₀ = 31 nM)
		MCF-7 IC₅₀ = 40 nM	Erlotinib
			EGFR (IC₅₀ = 80 nM)
			Lapatinib
			HER-2 (IC₅₀ = 26 nM)
24	EGFR, HER-2	SK-BR-3 (IC₅₀ = 0.78 µM)	EGFR (IC₅₀ = 6.15 nM)	195
		MCF-7 (IC₅₀ = 1.33 µM)	HER-2 (IC₅₀ = 9.78 nM)
		Lapatinib	Lapatinib
		SK-BR-3 (IC₅₀ = 1.12 µM)	EGFR (IC₅₀ = 0.41 nM)
		MCF-7 (IC₅₀ = 3.74 µM)	HER-2 (IC₅₀ = 10.41 nM)
25	EGFR, HER-2 and DHFR	MCF-7 IC₅₀ = 2.37 µM	EGFR (IC₅₀ = 0.122 nM)	196
		Sorafenib	HER-2 (IC₅₀ = 0.078 nM)
		MCF-7 IC₅₀ = 9.18 µM

Open in a new tab

Gomaa et al. reported a series of quinazoline-1,3,4-oxadiazole-2-thione hybrids, designed, synthesized, and evaluated for in vitro antiproliferative activity. Compounds 21a and 21b showed the highest potency, with IC₅₀ = 27 nM and 24 nM, respectively, against MCF-7 cells. Kinase profiling against EGFR, HER2, and BRAFV600E revealed that 21a and 21b are the most effective multi-target inhibitors. Compound 21a inhibited EGFR, HER2, and BRAFV600E with IC₅₀ values of 76, 33, and 48 nM, while 21b showed slightly stronger activity with IC₅₀ values of 71, 29, and 45 nM, respectively.¹⁹²

Salem et al. developed a series of pyrazolo[3,4-d]pyrimidine derivatives incorporating hydrazone, thiazole, thiadiazole, and triazole moieties as potential EGFR/HER2 dual inhibitors. The thiazole-containing compound 22 showed the strongest dual inhibition with IC₅₀ values of 90 nM (EGFR) and 80 nM (HER2). It also exhibited potent cytotoxicity against MCF-7 (2.84 µM), HepG-2 (3.90 µM), and HCT-116 (7.35 µM) cells and retained high activity against breast cancer cell lines (SKBr3, BT474, and MDA-MB-453). Flow cytometry confirmed that 22 induced apoptosis and G0/G1 cell-cycle arrest in MCF-7 cells. Molecular docking demonstrated strong binding of 22 within the ATP-binding sites of EGFR and HER2, with binding energies comparable to those of lapatinib; molecular dynamics simulations confirmed the stability of the compound complexes with EGFR and HER2.¹⁹³

Al-Wahaibi et al. reported that quinoline-based EGFR/HER2 dual inhibitors showed average antiproliferative activity (GI₅₀ = 25–82 nM) against the four tested cancer cell lines. Compound 23 was the most potent, with anti-breast cancer activity against MCF-7 (IC₅₀ = 23 nM) and inhibition of EGFR (IC₅₀ = 71 nM) and HER2 (IC₅₀ = 31 nM), outperforming erlotinib against EGFR but being slightly less potent than lapatinib against HER2.¹⁹⁴

Hao et al. designed and synthesized quinazoline-based EGFR/HER2 dual inhibitors using a heterocyclic tail strategy and evaluated their activity against all four HER family kinases. Among them, compound 24 emerged as the most potent and selective dual inhibitor, with IC₅₀ values of 6.15 nM (EGFR) and 9.78 nM (HER2), surpassing lapatinib. Most compounds in the series showed strong antiproliferative activity against breast cancer cells SK-BR-3 (IC₅₀ = 0.78 µM) and MCF-7 (IC₅₀ = 1.33 µM), with low toxicity to normal cells. Compound 24 also inhibited SK-BR-3 cell migration and significantly inhibited tumor growth with minimal toxicity in an SK-BR-3 xenograft model.¹⁹⁵

Sabry et al. designed a series of thiazole and imidazo[2,1-b]thiazole derivatives that were synthesized and evaluated for anticancer activity. Compound 25 arose as a key candidate, displaying potent dual inhibition of EGFR (IC₅₀ = 0.122 µM) and HER2 (IC₅₀ = 0.078 µM). Additionally, in vivo testing showed that compound 25 significantly reduced tumor volume and restored caspase-3 expression.¹⁹⁶

Irreversible dual EGFR/HER-2 kinase inhibitors

The utilization of irreversible dual EGFR/HER2 kinase inhibitors in oncological therapy is substantial in combating cancer resistance.¹⁹⁷ They covalently attach to the ATP-binding sites of EGFR and HER2 kinases, thereby inhibiting their signaling pathways regardless of mutations or inhibitor resistance.^198,199 These target HER2-positive breast cancer and non-small cell lung cancer (NSCLC).¹⁹⁹

Das et al. reported 4,6,7 trisubstituted quinazoline derivatives targeting EGFR/HER-2 kinases; the synthesized compounds (27–29) exhibited promising inhibitory activity against both enzymes. It is well observed that the compounds that act by irreversible or covalent interaction do not require an additional aromatic substitution at position 4 of the quinazoline nucleus to exhibit inhibition of HER-2 kinase. Although these three compounds bore simple aromatic moieties at position 4, they revealed promising inhibition of HER-2 kinase. Compound 28 demonstrated potent antiproliferative activity against the MDA-MB-453 BC cell line in subnanomolar concentrations, with an IC₅₀ of 0.62 nM (ref. 200) [Fig. 5a].

Yin et al. designed and synthesized novel compounds based on the oxazolo[4,5-g]quinazolin-2(1H)-one scaffold, bearing polar residues, including morpholino, piperazino, or piperidino moieties, oriented toward the hydrophobic back pocket. Some of these compounds demonstrated potent cellular and EGFR/HER2 inhibitory activities compared to lapatinib. As illustrated in Fig. 5b, the activities of these structurally unique compounds might be attributed to the electrophile reactivity of the terminal chloroacetoxy ethyl or bromoacetoxy ethyl moieties. Compound 30 bearing a morpholino moiety exhibited the most potent antiproliferative activity against the HER2-overexpressing breast cancer cell line (SK-Br3), with an IC₅₀ of 0.47 µM, and was 3-fold more potent against HER2 (IC₅₀ = 77 nM) than EGFR (IC₅₀ = 240 nM). Moreover, it showed a better safety profile than lapatinib by exhibiting a higher inhibitory concentration exceeding 1000 µM, lapatinib IC₅₀ is equal to 12.1 µM against human embryonic lung fibroblast cell line (HELF) normal cells.²⁰¹

Lin et al. designed and synthesized novel 4-anilinoquinazoline derivatives incorporating phosphoramide mustard functionality as an active pharmacophoric moiety of the DNA alkylating agent cyclophosphamide, as demonstrated in Fig. 6. The synthesized conjugates were designed to target EGFR/HER2/DNA without the acrolein-induced nephrotoxicity associated with cyclophosphamide. The synthesized compounds exhibited more potent antiproliferative activity against tumor cells with high HER2 levels (SK-BR-3 breast cancer cells) than against cells with low HER2 levels (MDA-MB-468 TNBC cells), suggesting that the inhibitory effects may be mediated by HER2 regulation. Conjugate compound 31 demonstrated the most potent dual inhibitory activity against EGFR and HER2 kinases with IC₅₀ values of 7.4 nM and 82 nM, respectively, and induced DNA damage in SK-BR-3 and MDA-MB-468 breast cancer cells.²⁰²

EGFR/HER-2 & HDAC hybrid inhibitors

The hybrid molecules demonstrated greater inhibitory activity against the original lapatinib targets, EGFR/HER2, as well as newly acquired activity against HDAC.^126,203 Histone deacetylase (HDAC) inhibitors were reported to synergize with tyrosine kinase inhibitors by suppressing proliferation and inducing apoptosis in tumor cells, making tumor cells more susceptible to RTK inhibitor treatment and even overcoming RTK inhibitor resistance.^204–206

Mahboobi et al. combined the structural features of the EGFR/HER-2 dual inhibitor lapatinib with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors. The two hybrid molecules 32 and 33 demonstrated selective inhibition of both targets and potent cellular activity against human BC cell lines, including HER-2-overexpressing SKBR3 and SKOV3 (Fig. 7).²⁰³

Lapatinib-based PROTACs induced EGFR/HER2 degradation

Degradation of the kinase itself, rather than inhibition of the domain, could offer advantages, such as reduced drug exposure time needed to suppress signaling transduction, longer sustained growth inhibition, and reduced emergence of resistance through mutation or by restoring signaling crosstalk with other downstream pathways.²⁰⁷ Proteolysis Targeting Chimera (PROTAC) has emerged recently as an effective strategy for the targeted degradation of endogenous proteins.²⁰⁸ Generally, Fig. 8 demonstrates the chimeric molecules, which are bifunctional molecules that bear three fragments, a ligand with high binding affinity to a certain target protein, another ligand able to recruit an E3 ligase such as Thalidomide (34), Pomalidomide (35), Lenalidomide (36), and VH032 (37), and a linker between these two ligands.²⁰⁹

Crews et al. reported a developed EGFR-targeting PROTAC by conjugating the dual EGFR/HER2 inhibitor lapatinib to the VH032 ligand, which binds the E3 ligase VHL. Chimeric series 38a,b, which utilizes a diethylene glycol linker to VH032 (37), induces EGFR/HER2 degradation at low nanomolar concentrations and demonstrates potent antiproliferative activity against the HER2-driven breast cancer cell line SKBr3, with an IC₅₀ of 102 nM. However, the linker expansion with an additional ethylene glycol moiety yielded the chimeric compound 38b, which selectively degraded EGFR while sparing HER2.²¹⁰

VEGFR inhibitors

The vascular endothelial growth factor receptor (VEGFR) system is a key regulator of angiogenesis in cancer cells, and blocking its signaling is one of the most promising approaches to inhibiting angiogenesis and subsequent cancer cell growth.²¹¹ VEGFR-2, a member of the receptor tyrosine kinase family, is a key mediator of tumor angiogenesis.²¹²

VEGFR-active TKIs further illustrate this issue, while antiangiogenic activity is commonly exploited in metastatic tumors, as exemplified by VEGFR inhibitors such as sunitinib, pazopanib, axitinib, lenvatinib, and cabozantinib.^213,214

The efficacy of utilizing VEGFR-2 inhibitors in breast cancer treatment was revealed by the study of sorafenib (45), which synergized with radiation to kill hypoxic breast cancer cells MDA-MB-231 and MCF-7, inducing G2/M arrest and apoptosis, besides preferentially eliminating breast cancer stem cells, suppressing HIF-1α/MMP-2 signaling, and inhibiting mammosphere formation, angiogenesis, and metastasis.²¹⁵

Li et al. designed and synthesized a series of 3-aryl-quinoline derivatives to target the ERα and VEGFR-2 by combining the structural features of ERα inhibitor 40 and VEGFR-2 inhibitor cabozantinib (41) to eliminate the disadvantages of SERMs (selective estrogen receptor modulators). In Fig. 9a, Compounds 42 and 43 displayed high ERα-binding affinities and relative VEGFR-2 inhibitory activity. Moreover, these two compounds exhibited excellent antiproliferative activity against MCF-7 and HUVEC cell lines, with IC₅₀ values in the low micromolar range (1–8 µM), compared with IC₅₀ values for tamoxifen and raloxifene (16.7 and 12.5 µM, respectively). Further study confirmed that compound 43 can reduce PgR mRNA expression, arrest the cell cycle in MCF-7 BC cells, and inhibit cell migration. Overall, based on the biological activity data, compound 43 can be chosen as a potential anticancer lead compound for further study.²¹⁶

Various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogs were rationally designed, synthesized by Luo et al., and evaluated as a chemotype of dual ERα and VEGFR-2 inhibitors. Fig. 9b demonstrates that the optimization of the hit compound led to compound 44 exhibiting an IC₅₀ for ERα binding affinity of 2.19 µM with potent inhibition on VGFR-2. In the RT-PCR assay, compound 44 exerted significant antiestrogenic effects by suppressing progesterone receptor (PgR) mRNA expression in MCF-7 cells.²¹⁷

As listed in Table 4, Elgammal et al. published the design and synthesis of a series of dihydrothiadiazole derivatives, which were evaluated against MDA-MB-231 and MCF-7 breast cancer cells. Compound 46 is a promising dual VEGFR-2/B-Raf inhibitor for breast cancer therapy, with activity against MDA-MB-231 and MCF-7 (IC₅₀ values of 11.60 and 18.07 µM, respectively), compared with sorafenib (IC₅₀ values of 7.64 and 7.26 µM, respectively). Enzymatic assays confirmed dual inhibition of VEGFR-2 (IC₅₀ = 0.17 µM) and B-Raf (IC₅₀ = 0.083 µM).²¹⁸

Table 4. VEGFR-2 inhibitors targeting BC.

Compound no.	Targets	Activity against BC cells	VEGFR-2 IC₅₀	References
46	VEGFR-2 & B-Raf	MDA-MB-231 (IC₅₀ = 11.60 µM)	0.17 µM	218
		MCF-7 (IC₅₀ = 18.07 µM)	Sorafenib
		Sorafenib	0.10 µM
		MDA-231 (IC₅₀ = 7.64 µM)
		MCF-7 (IC₅₀ = 7.26 µM)
48	VEGFR-2	MCF-7 IC₅₀ = 1.44 µM	0.078 µM	219
		Sunitinib MCF-7 IC₅₀ = 4.77 µM	Sunitinib
			0.139 µM
49	VEGFR-2	MDA-MB-231 (IC₅₀ = 21.68 µM)	62.26 nM	220
49	VEGFR-2	MCF-7 (IC₅₀ = 35.81 µM)	Sorafenib IC₅₀ = 53.32 nM	220
50	VEGFR-2 & EGFR	GI₅₀ values of (1.16–1.64 µM) range against breast cancer cells (MCF7, MDA-MB-231, HS 578T, BT-549, T-47D, and MDA-MB-468)	185 nM	58
50	VEGFR-2 & EGFR		Sorafenib IC₅₀ = 65 nM	58
51	VEGFR-2 & EGFR	MDA-MB-231 (IC₅₀ = 7.33 µM)	6.72 µM	221
51	VEGFR-2 & EGFR	Doxorubicin (IC₅₀ = 2.22 µM)	Sorafenib IC₅₀ = 0.47 µM	221
52	VEGFR-2 & EGFR	MDA-MB-231 (IC₅₀ = 8.13 µM)	50.31 nM	222
		MCF-7 (IC₅₀ = 11.72 µM)	Sorafenib IC₅₀ = 53.28 nM
		Sorafenib
		MDA-MB-231 (IC₅₀ = 7.64 µM)
		MCF-7 (IC₅₀ = 7.26 µM)
53	VEGFR-2 & EGFR	MCF-7 (IC₅₀ = 30 nM)	2.4 nM	223
		Erlotinib	Sorafenib
		MCF-7 (IC₅₀ = 40 nM)	IC₅₀ = 0.14 nM
54	VEGFR-2 & EGFR	MCF-7 (IC₅₀ = 36 nM)	3.5 nM	224
		Erlotinib	Sorafenib
		MCF-7 (IC₅₀ = 40 nM)	IC₅₀ = 0.17 nM

Open in a new tab

Indoline-2-one analogs introduced by Abdelgawad et al. were designed to modulate VEGFR-2 and to assess their activity in breast cancer cells by replacing the diethylamine moiety of sunitinib (47) with a phenyl ring and altering the linker to increase the number of hydrogen-bond donors. Within this series, 48 stood out for its strong anti-breast cancer activity against MCF-7 (IC₅₀ = 1.44 µM) and its inhibition of VEGFR-2 (IC₅₀ = 0.078 µM), surpassing the reference sunitinib, which has MCF-7 IC₅₀ = 4.77 µM and VEGFR-2 IC₅₀ = 0.139 µM.²¹⁹

A series of quinoxaline derivatives was developed by Eissa et al. to target VEGFR-2. Compound 49 showed selective cytotoxicity against MDA-MB-231 (IC₅₀ = 21.68 µM) and MCF-7 (IC₅₀ = 35.81 µM) with low toxicity toward normal WI-38 and WISH cells, indicating a favorable therapeutic window. Compound 49 inhibited VEGFR-2 (IC₅₀ = 62.26 nM), comparable to sorafenib. It suppressed MDA-MB-231 cell migration.²²⁰

The 6,7-dimethoxyquinazoline scaffold provides a significant core for the tyrosine kinase inhibitors, and a series of 6,7-dimethoxyquinazoline compounds designed and synthesized by Aref et al., compound 50 demonstrated consistent antiproliferative activity across a panel of breast cancer cell lines, including MCF-7, MDA-MB-231, HS-578T, BT-549, T-47D, and MDA-MB-468, with GI₅₀ values ranging from 1.16 to 1.64 µM. Enzymatic assays further revealed its dual kinase-inhibition profile, demonstrating activity against VEGFR-2 (IC₅₀ = 0.185 µM) and EGFR (IC₅₀ = 0.214 µM). These findings highlight compound 50 as a promising dual EGFR/VEGFR-2 inhibitor with broad-spectrum efficacy across diverse breast cancer subtypes.⁵⁸

Two series of quinazoline–benzohydrazide and quinazoline–benzothiazole hybrids were developed by El Hamaky et al. as dual EGFR/VEGFR-2 inhibitors, with compound 51 showing the strongest activity. Compound 51 displayed potent antiproliferative effects in breast cancer cells, particularly in TNBC MDA-MB-231 cells (IC₅₀ = 7.33 µM), inducing G0/G1 arrest and apoptosis by modulating Bax/Bcl-2 and activating caspases.²²¹

Thieno[2,3-d]pyrimidine derivatives were developed by Yousef et al. as dual EGFR/VEGFR-2 inhibitors, and compound 52 with N-allyl-4-piperazine-1-carboxamide side chain showed notable cytotoxicity against MDA-MB-231 (IC₅₀ = 8.13 µM) and MCF-7 (IC₅₀ = 11.72 µM) with lower toxicity to WI-38 cells, comparable to sorafenib. It potently inhibited EGFR (IC₅₀ = 5.42 nM) and VEGFR-2 (IC₅₀ = 50.31 nM), and suppressed MDA-MB-231 cell migration.²²²

The series of 1,2,3-triazole/1,2,4-oxadiazole hybrids was developed as promising dual EGFR/VEGFR-2 inhibitors. Compound 53 exhibited strong antiproliferative activity and potent kinase inhibition, with a VEGFR-2 IC₅₀ of 2.4 nM and cytotoxicity against MCF-7 cells (IC₅₀ = 30 nM). These results identify 53 as a promising VEGFR-2-driven anticancer candidate within this series.²²³

The study by Al-Wahaibi et al. evaluated pyrimidine derivatives for anticancer activity and identified compound 54 as a leading derivative. It showed strong antiproliferative potency, with an average GI₅₀ of 35 nM across the four tested cell lines, comparable to erlotinib, and exhibited activity against breast cancer cells (MCF-7; IC₅₀ = 36 nM). Moreover, the enzymatic assay showed dual inhibition of EGFR (IC₅₀ = 84 nM) and VEGFR-2 (IC₅₀ = 3.50 nM) kinases.²²⁴

VEGFR-2/HDAC inhibitors

Peng et al. designed and synthesized a series of vandetanib- and vorinostat-based hybrids targeting VEGFR-2 and HDAC enzymes. Compound 57 [Fig. 10] exhibited the most potent inhibitory activity against HDAC with an IC₅₀ of 2.2 nM and a strong inhibitory effect against VEGFR-2 with an IC₅₀ of 74 nM compared to the starting leads (vandetanib & vorinostat). It also demonstrated the most potent inhibitory activity against a human breast cancer cell line, MCF-7, with an IC₅₀ of 0.58 µM.²²⁵

PDGFR kinase inhibitors

PDGFRα is frequently overexpressed in aggressive breast cancer subtypes, especially triple-negative and inflammatory forms, and its activation drives key oncogenic processes, including cell proliferation, angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, and therapeutic resistance.^226,227

As depicted in Fig. 11, CP-673451 (58), a highly selective PDGFRα/β inhibitor, has demonstrated potent anti-tumor activity in breast cancer models. Preclinical studies showed that CP-673451 effectively suppressed tumor growth in xenograft models and induced growth arrest in PDGFR-driven cell lines, including MDA-MB-453 and MFM-223. Moreover, its combination with AKT or SGK1 blockade exhibited synergistic antiproliferative effects, underscoring the therapeutic potential of targeting PDGFR signaling in breast cancer progression.²²⁸

Crenolanib (59), a highly selective type I inhibitor of PDGFRα/β, as well as FLT3, binds active “DFG-in” conformation, has been shown to exert potent anti-tumor effects in breast cancer models by disrupting an autocrine PDGF-PDGFRα signaling loop; it induces G₂ cell-cycle arrest in inflammatory breast cancer cells and dramatically reduces tumor emboli formation in a 3D in vitro model of invasion, highlighting its capacity to impair both proliferation and metastatic potential via PDGFRα inhibition.²²⁹ Crenolanib demonstrates strong efficacy against mutated PDGFRα, including the clinically relevant T674I gatekeeper mutation. Unlike many type II inhibitors that lose potency against this resistant mutant, Crenolanib binds the active (DFG-in) conformation of PDGFRα and retains high affinity (PDB: 6JOJ).²³⁰

Compound 60 showed the most potent activity against MDA-MB-231 cells. The results suggested that PDGFRβ was the potential target. Compound 60 demonstrated moderate inhibition of PDGFRβ (IC₅₀ PDGFRβ = 7.8 µM). In vitro experiments revealed that it attenuated metastasis by PDGFRβ inhibition-induced autophagy and could enhance autophagy-related cell death through the AKT-MAPK feedback loop in TNBC MDA-MB-231 cells.²³¹

Met inhibitors

c-Mesenchymal epithelial transition factor (c-Met), is an RTK that presents a promising target for breast cancer therapy due to its involvement in cancer initiation and progression, including proliferation, survival, migration, stemness, and resistance to radiation and chemotherapy.^232,233

Simiczyjew et al. demonstrated that dual inhibition of MET and EGFR using foretinib plus lapatinib synergistically suppressed TNBC cell viability, induced G2/M arrest, and downregulated p-AKT signaling.²³⁴

The study by Wang et al. exhibited that dual inhibition of c-Met and HDAC is a promising anticancer strategy through designing a series of c-Met/HDAC dual inhibitors, among which compound 62 potently inhibited c-Met (IC₅₀ = 28.92 nM) and HDAC (85.68% at 1 µM) and suppressed proliferation in three breast cancer cell lines, MDA-MB-231, MDA-MB-453, and MDA-MB-468 (IC₅₀ = 3.57, 5.47, and 1.25 µM, respectively). Moreover, compound 62 induced G0/G1 arrest, promoted apoptosis, and reduced invasion in the TNBC cell line MDA-MB-231 by concurrently blocking the c-Met and HDAC pathways, supporting this dual-target strategy for breast cancer therapy²³⁵ [Fig. 12].

A series of dual PARP1/c-Met hybrid inhibitors was reported by Sun et al., combining a quinoline scaffold with the olaparib structure. Remarkably, compound 63 displayed potent inhibition of both PARP1 (IC₅₀ = 3.3 nM) and c-Met (IC₅₀ = 32.2 nM) and showed strong antiproliferative activity in HR-proficient and PARP1-resistant cancer cells. Notably, compound 63 exhibited superior antitumor efficacy compared with Olaparib, Crizotinib, or their combination in MDA-MB-231 xenograft models, supporting the potential of PARP1/c-Met dual inhibition to overcome PARP inhibitor resistance.²³⁶

Naguib et al. designed and synthesized a series of coumarin–thiazole hybrids as dual STAT-3/c-MET inhibitors, and compound 64 showed notable activity, with a GI₅₀ value of 1.43 µM in MDA-MB-231 cells and 2.78 µM in other tested lines. Compound 64 inhibited STAT-3 (IC₅₀ = 4.7 µM) and c-MET (IC₅₀ = 12.67 µM), demonstrating its potential as a dual-target anticancer agent.²³⁷

FGFR inhibitors

Fibroblast Growth Factor Receptors (FGFRs) and their numerous FGF ligands are often dysregulated in breast cancer progression and are one of the causes of resistance to treatment in breast cancer.²³⁸ The crystal structures of ligand interactions with FGFR1 (PDB: 4RWL) and FGFR1 (PDB: 6MZW) [Fig. 13] offer significant insights into their binding mechanisms and potential outcomes for targeted inhibition strategies. In FGFR1-lucitanib complex (PDB: 4RWL), the ligand is located within the ATP-binding region, forming significant interactions. Standard H-bonds with critical residues such as ASP641 and ALA564 reinforce the binding. These interactions demonstrate a typical reversible binding profile for type I kinase inhibitors. The ligand's planar structure and elongated aromatic core promote hydrophobic interactions, enhancing its binding affinity and selectivity for FGFR1. FGFR1-futibatinib co-crystalized structure (PDB: 6MZW) demonstrates an alternative mechanism of action, distinguished by the covalent interaction of futibatinib with the cysteine residue CYS488. The covalent mode of FGFR1 inhibition is especially beneficial for targeting kinase mutations that could resist reversible inhibitors.^239,240

Lucitanib (65) is a multi-kinase inhibitor targeting FGFR1-3, VEGFR1-3, and PDGFRα/β, demonstrating significant tumor growth reduction in various xenograft models and has modest antitumor activity in HR⁺/HER2⁻ metastatic BC.^241,242 Its potent anti-angiogenic properties contribute to its effectiveness in inhibiting tumor progression.²⁴¹ Futibatinib (66), a selective, irreversible inhibitor of FGFR1–4, demonstrated significant inhibition of tumor growth primarily in breast cancer models harboring FGFR2 amplification.^243,244

Chen et al. reported that compound 67 showed high selectivity for FGFR1, with an IC₅₀ of 19 nM across a panel of 20 tyrosine kinases. The compound effectively suppressed cell proliferation in multiple cancer models, with particularly noticeable activity against breast cancer cells, reducing migration and invasive capacity by inhibiting FGFR1 phosphorylation and thereby attenuating its downstream signaling cascade.²⁴⁵ Ashraf-Uz-Zaman et al. reported a series of more than 40 urea-based analogs that were screened against the TNBC breast cancer cell line, and the findings revealed that compound 68 is active against MDA-MB-231 cells and IC₅₀ is equal to 7.7 µM, with the ability to penetrate the BBB in vivo to overcome brain metastasis, and further mechanistic study revealed FGFR1.²⁴⁶

In animal models and in cancer patients, the development and therapeutic evaluation of FGFR4-selective inhibitors, including BLU9931 (69), have demonstrated promising results in inhibiting FGFR4 signaling overexpression in cancer.²⁴⁷ Mo et al. reported the design and synthesis of some 2-aminopyrimidine derivatives as highly selective FGFR4 inhibitors. Compound 70 exhibited potent and selective inhibitory activity against FGFR4 with an IC₅₀ value of 2.6 nM compared to BLU9931 (IC₅₀ = 4 nM). Compound 70 selectively suppressed the proliferation of BC cells (MDA-MB-453) with dysregulated FGFR4 signaling, with an IC₅₀ of 0.38 µM. However, the antiproliferative activity against cancer cells with low FGFR4 expression (MDA-MB-231 and MCF-7) was not significant (IC₅₀ > 10 µM).²⁴⁸

Bruton tyrosine kinase (BTK)

Bruton tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a cytoplasmic intracellular signaling molecule that transmits signals from a variety of cell-surface molecules and is involved in the regulation of maturation, survival, migration, and activation of B cells and microglia.^249,250 BTK inhibitors, originally developed for B-cell malignancies, have shown potential in breast cancer treatment.

Ibrutinib (71), a first-generation BTK inhibitor, has demonstrated efficacy in inhibiting breast cancer progression and metastasis.²⁵¹ Studies indicate that ibrutinib can prevent the emergence of lapatinib-resistant breast cancer clones, potentially by modulating HER2 kinase activity.²⁵¹ Ibrutinib suppresses tumor progression and metastasis in breast cancer by facilitating the maturation of dendritic cells from myeloid-derived suppressor cells, thereby presenting itself as a potential innovative therapeutic drug for breast cancer treatment.²⁵² Moreover, ibrutinib has been found to inhibit ERBB receptor tyrosine kinases, including HER2 and EGFR, suggesting its potential utility in HER2-positive breast cancers.²⁵³ Zanubrutinib (72), a second-generation BTK inhibitor, demonstrated antiproliferative effects in HER2-positive BC cell lines. Additionally, Dostálová et al. reported that it effectively inhibited the HER2 signaling pathway, suggesting its potential as a therapeutic agent for HER2-positive breast cancers.²⁵⁴ The co-crystallized structures of Ibrutinib (PDB: 5P9J; Fig. 14a) and Zanubrutinib (PDB: 6 J6M; Fig. 14b) with BTK elucidate essential molecular interactions that highlight their significant inhibitory efficacy.^255,256 Ibrutinib covalently binds to the Cys481 residue in the BTK active site, creating a stable, irreversible binding. The crystal structure reveals further non-covalent interactions, encompassing hydrogen bonds with THR474, GLU475, TYR476, and MET477 (ref. 255). Zanubrutinib exhibits interactions similar to those of Ibrutinib, forming a covalent bond with Cys481. Moreover, the structural core modification in the hinge region significantly enhances the binding affinity and selectivity for BTK over other TEC, EGFR, and Src family kinases.²⁵⁶

FAK inhibitors

Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, is overexpressed and activated in several advanced-stage solid cancers.²⁵⁷ FAK enhances tumor progression and metastasis by affecting both cancer and stromal cells within the tumor microenvironment.²⁵⁸ FAK-driven tumor cell proliferation is linked to the PI3K/AKT/mTOR signaling pathway, one of the most disrupted pathways in cancer.²⁵⁹ Consequently, inhibiting FAK reduces AKT-mTOR signaling, suppresses Wnt1-induced basal-like breast cancer progression, and promotes apoptosis.²⁵⁹

TAE226 (73) is a dual inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor 1 receptor (IGF-1R). It was reported to be evaluated in a panel of cancer cell lines and showed MIA PaCa-2 human pancreatic tumor and 4T1 murine breast tumor models.²⁶⁰

Wang et al. described a group of diphenylpyrimidine derivatives that are strongly active against FAK, as illustrated in Fig. 15. Compounds 74a,b displayed potent anti-FAK enzymatic activity (IC₅₀ = 5.17 nM and 2.58 nM, respectively). Compound 74a also exhibited strong antiproliferative activity against several cancer cells, including the multidrug-resistant BC cell line MCF-7/ADR (IC₅₀ = 0.59 µM).²⁶¹

Groendyke et al. reported a series of tricyclic pyrimidothiazolodiazepinone cores with significant efficacy and selectivity against FAK. As shown in Fig. 15, SAR studies revealed modifications to the thiazole, diazepinone, and aniline moieties, thereby identifying the lead compound BJG-03-025 (76). Compound BJG-03-025 (76) exhibited notable inhibition of FAK (IC₅₀ = 20 nM), remarkable kinome selectivity, efficacy in 3D-binding breast and stomach cancer models, and advantageous pharmacokinetic characteristics in murine subjects. BJG-03-025 (76) is a potent chemical probe for assessing FAK-dependent biology. The SAR study indicated that thiazole nitrogen is essential for H-bonding, whereas N-alkylation of the amide enhances pharmacokinetics. The inhibition of FAK in compound (76) (IC₅₀ = 20 nM) was greater compared to compound (75) (62.2 nM). Additionally, compound BJG-03-025 (76) showed potent activity against MDA-MB-231 TNBC cells with an IC₅₀ of 3.6 µM, and this activity was potentiated by the N-ethyl substitution in compound (77).²⁶²

SRC inhibition

c-Src is a non-receptor protein tyrosine kinase, known as proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, encoded by the SRC gene, and is a member of the Src family kinases (SFKs).²⁶³ It is crucial for various cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis.^263,264

c-Src stimulates multiple downstream signaling pathways by phosphorylating critical proteins by conveying signals from diverse cell-surface receptors, including integrins and G protein-coupled receptors (GPCRs).²⁶⁵ Furthermore, overexpression of c-Src amplifies EGFR-mediated signaling pathways, indicating a reciprocal relationship in which EGFR and c-Src mutually potentiate each other's functions.²⁶⁶ Notably, elevated expression levels of c-Src have been observed in human breast cancer tissues compared to normal breast tissues, highlighting its potential role in tumor progression.²⁶⁷ c-Src activity was reported to be the main mode of resistance to Herceptin, a first-line therapy for HER2⁺ breast cancer.²⁶⁸

Fraser et al. designed and synthesized pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases over ABL kinase. The design was developed through an iterative combination of ligand-based design and phenotypic screening, demonstrating the importance of replacing the side chain of the multi-kinase inhibitor 78 with the 1-ethyl-N,N-dimethylpiperidin-4-amine moiety in the hydrophobic region, thereby shifting selectivity toward c-Src. This strategy led to the discovery of compound (79; Fig. 16) as a potent antiproliferative lead against TNBC (MDA-MB-231, IC₅₀ = 9 nM) with a subnanomolar IC₅₀ for SRC, with approximately a 1000-fold higher concentration required to inhibit ABL.²⁶⁹

Compound 82 exhibited potent antiproliferative activity against breast cancer cell lines MDA-MB-231 (IC₅₀ = 0.812 µM), T47D (IC₅₀ = 1.03 µM), and MCF-7 (IC₅₀ = 0.568 µM), while showing minimal toxicity toward normal cells. Target validation studies demonstrated that 82 inhibited c-Src in a dose-dependent manner (IC₅₀ = 302 nM), outperforming the reference inhibitor bosutinib (81) (IC₅₀ = 446 nM). Moreover, 82 increased intracellular ROS levels, disrupted mitochondrial membrane potential, induced apoptosis, and arrested the cell cycle beyond the G1 phase.²⁷⁰

Wang et al. developed a series of dual Src/BRD4 inhibitors by linking JQ1 (83) and dasatinib (80) with various linkers, as shown in Fig. 17, and evaluated their efficacy against TNBC in both in vitro and in vivo settings. This series was designed based on the essential interactions observed in the co-crystallized structures of BRD4 (PDB: 3MXF) and Src (PDB: 3G5D). The hybrid structure HL403 (84) demonstrated IC₅₀ values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. HL403 exhibited potent antiproliferative activity and effectively suppressed MDA-MB-231 cell invasion in vitro (IC₅₀ = 34 nM). The anti-tumor efficacy of HL403 (84) was validated in a mouse MDA-MB-231 xenograft model, achieving a tumor growth inhibition rate (TGI) of 70.7%, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0%).²⁷¹

Brandvold et al. introduced an approach that expanded the conventional inhibitor design of the non-selective compound 85 by incorporating a phenyltriazole side chain (compound 86) intended to engage the phosphate-binding loop of c-Src. Using a selective inhibitor, the study shows that targeting c-Src is more effective than broad pan-kinase inhibition in suppressing cancer cell growth. It further demonstrates that off-target inhibition of c-Abl, a common feature of many c-Src inhibitors, can enhance oncogenic cell proliferation.²⁷²

Ko et al. reported a synergistic effect between the HDAC inhibitor panobinostat (10 nM) and the selective Src inhibitor 86 in SK-BR-3 breast cancer cells (Fig. 18), resulting in enhanced growth inhibition and apoptosis. Since SK-BR-3 cell proliferation depends on c-Src activity, the study was repeated using another HDAC inhibitor, vorinostat, combined with 86 to assess whether this potentiation was generalizable. The combination of compound 86 and vorinostat exhibited marked synergy, reducing the GI₅₀ in SK-BR-3 cells to 0.8 µM, compared with 4.8 µM for compound 86 alone. Building on these findings, Soellner et al. designed chimeric molecules targeting both c-Src kinase and HDACs. Chimera 88 (Fig. 18) exhibited potent antiproliferative activity across multiple breast cancer cell lines, including MCF-7, HER2⁺ SK-BR-3, and TNBC cells (HS 578T and MDA-MB-231). Notably, compound 88 showed superior potency in SK-BR-3 cells (GI₅₀ = 0.2 µM), outperforming the dual–drug combination (GI₅₀ = 0.8 µM).²⁷³

JAK inhibition

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway.²⁷⁴ JAK2 selectively phosphorylates the signal transducer and activator of transcription (STAT) 3, and the JAK2-STAT3 signaling pathway is crucial for cancer progression and metastasis.²⁷⁵ In tamoxifen-resistant MCF-7 cells (TAMR-MCF-7), STAT3 signaling is driven by EGFR and Src activation, suggesting that STAT3 is a promising therapeutic target.²⁷⁶ Additionally, elevated nuclear p21 (Cip1) appears to play a critical role in STAT3-inhibited cell death in these cells.²⁷⁶

Ruxolitinib (89), a potent JAK2 inhibitor, was demonstrated to attenuate STAT3 phosphorylation and the proliferation of TAMR-MCF-7 cells.²⁷⁷ Clinically approved JAK2 inhibitors showed limited activity in TNBC, except for fedratinib (90), which potently inhibited the proliferation of MDA-MB-231 and HS578T cells (IC₅₀ < 2 µM), suppressed colony formation, downregulated MYC and cyclin D1, and induced PARP-mediated apoptosis.²⁷⁸

Yang et al. introduced a pharmacophore-merged approach using vorinostat, as a Pan HDAC inhibitor, and pacritinib (91) (a JAK-2/FLT3 inhibitor) to create bispecific single molecules with dual JAK and HDAC inhibition [Fig. 19]. Compound 92 inhibits JAK2 and HDAC6 with low nanomolar potency. It also exhibited strong antiproliferative activity in breast cancer cell lines (MDA-MB-231 & MCF-7) and other hematological cancer cell lines.²⁷⁹

Conclusion

This review highlights medicinal chemistry strategies for developing small-molecule tyrosine kinase inhibitors (TKIs) for breast cancer by integrating binding-mode classification, scaffold selection, and structure-guided optimization. Targeting diverse kinases, including HER2, EGFR, FGFR, PDGFR, VEGFR-2, Src, and BTK, has produced versatile heterocyclic scaffolds that strengthen hinge interactions, enable covalent engagement, and support rational multi-target design. Incorporating non-kinase elements into TKI scaffolds, such as HDAC pharmacophores, PROTAC-based degraders, irreversible groups, and kinase/non-kinase hybrid designs, further enhances anticancer efficacy and helps overcome pathway-driven resistance.

Despite substantial progress, long-term therapeutic success remains limited by tumor heterogeneity, adaptive signaling, acquired resistance, and metastatic spread, particularly to the brain. Future efforts should focus on dual- and multi-kinase inhibitors that suppress bypass pathways, supported by kinome-wide selectivity profiling and advanced computational and machine-learning tools to accelerate scaffold optimization. Expanding structure-based design across various conformations and diversifying scaffolds will be essential. Integrating these medicinal-chemistry principles with translational biomarkers and mechanism-guided combinations is expected to advance the development of next-generation TKIs and degraders with improved selectivity, durability, and efficacy in metastatic and treatment-refractory breast cancer.

Author contributions

Engaged in research design: H. I. A. and T. A. E.; conducted data analysis: T. A. E. and M. M. A. A.; authored or contributed to the composition of the manuscript: T. A. E., M. M. A. A., and H. I. A.

Conflicts of interest

The authors disclose no conflicts of interest.

Acknowledgments

This research was funded by the start-up fund at Texas A&M Health Sciences Center (to H. I. A., award number 121500-35558).

Data availability

No new data were generated or analyzed in support of this review article. Therefore, no research data is associated with this manuscript.

References

Bray F. Laversanne M. Sung H. Ferlay J. Siegel R. L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J. Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
Wilkinson L. Gathani T. Understanding breast cancer as a global health concern. Br. J. Radiol. 2022;95(1130):20211033. doi: 10.1259/bjr.20211033. [DOI] [PMC free article] [PubMed] [Google Scholar]
National Cancer Institute website, Cancer Stat Facts: Female Breast Cancer, 2024, Available from: https://seer.cancer.gov/statfacts/html/breast.html
Tufail M. Cui J. Wu C. Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches. Am. J. Cancer Res. 2022;12(7):2920–2949. [PMC free article] [PubMed] [Google Scholar]
Orrantia-Borunda E., Anchondo-Nuñez P., Acuña-Aguilar L. E., Gómez-Valles F. O. and Ramírez-Valdespino C. A., Subtypes of Breast Cancer, in Breast Cancer, H. N. Mayrovitz, Exon Publications, Brisbane (AU), Copyright: The Authors.; The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced., 2022 [Google Scholar]
Orrantia-Borunda E., Anchondo-Nuñez P., Acuña-Aguilar L. E., Gómez-Valles F. O. and Ramírez-Valdespino C. A., Subtypes of Breast Cancer. Cancer B, ed. H. N. Mayrovitz, Exon Publications, Brisbane, 2022 [PubMed] [Google Scholar]
Eroles P. Bosch A. Alejandro Pérez-Fidalgo J. Lluch A. Molecular biology in breast cancer: Intrinsic subtypes and signaling pathways. Cancer Treat. Rev. 2012;38(6):698–707. doi: 10.1016/j.ctrv.2011.11.005. [DOI] [PubMed] [Google Scholar]
Hsu J. L. Hung M. C. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016;35(4):575–588. doi: 10.1007/s10555-016-9649-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Miziak P. Baran M. Błaszczak E. Przybyszewska-Podstawka A. Kałafut J. Smok-Kalwat J. Dmoszyńska-Graniczka M. Kiełbus M. Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers. 2023;15(19):4689. doi: 10.3390/cancers15194689. [DOI] [PMC free article] [PubMed] [Google Scholar]
Rios-Hoyo A. Xiong K. Dai J. Yau C. Marczyk M. Garcia-Milian R. Wolf D. M. Huppert L. A. Nanda R. Hirst G. L. Cobain E. F. van ’t Veer L. J. Esserman L. J. Pusztai L. Hormone Receptor–Positive HER2-Negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple-Negative Breast Cancers. Clin. Cancer Res. 2025;31(2):403–413. doi: 10.1158/1078-0432.CCR-24-1553. https://dx.doi.org/10.1158/1078-0432.Ccr-24-1553 [DOI] [PMC free article] [PubMed] [Google Scholar]
Mu Y. Meng Y. Du Y. Liu X. Zhang J. Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer. Thorac. Cancer. 2023;14(34):3381–3388. doi: 10.1111/1759-7714.15130. [DOI] [PMC free article] [PubMed] [Google Scholar]
García-García C. Ibrahim Y. H. Serra V. Calvo M. T. Guzmán M. Grueso J. Aura C. Pérez J. Jessen K. Liu Y. Rommel C. Tabernero J. Baselga J. Scaltriti M. Dual mTORC1/2 and HER2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-HER2 Therapy. Clin. Cancer Res. 2012;18(9):2603–2612. doi: 10.1158/1078-0432.CCR-11-2750. https://dx.doi.org/10.1158/1078-0432.Ccr-11-2750 [DOI] [PubMed] [Google Scholar]
Swain S. M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug Discovery. 2023;22(2):101–126. doi: 10.1038/s41573-022-00579-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
Oh D. Y. Bang Y. J. HER2-targeted therapies - a role beyond breast cancer. Nat. Rev. Clin. Oncol. 2020;17(1):33–48. doi: 10.1038/s41571-019-0268-3. [DOI] [PubMed] [Google Scholar]
Escrivá-de-Romaní S. Arumí M. Bellet M. Saura C. HER2-positive breast cancer: Current and new therapeutic strategies. Breast. 2018;39:80–88. doi: 10.1016/j.breast.2018.03.006. [DOI] [PubMed] [Google Scholar]
Nunnery S. E. Mayer I. A. Balko J. M. Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis. Cancer J. 2021;27(1):2–7. doi: 10.1097/PPO.0000000000000494. https://dx.doi.org/10.1097/ppo.0000000000000494 [DOI] [PMC free article] [PubMed] [Google Scholar]
Lehmann B. D. Bauer J. A. Chen X. Sanders M. E. Chakravarthy A. B. Shyr Y. Pietenpol J. A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 2011;121(7):2750–2767. doi: 10.1172/JCI45014. https://dx.doi.org/10.1172/jci45014 [DOI] [PMC free article] [PubMed] [Google Scholar]
Zangardi M. L. Spring L. M. Nagayama A. Bardia A. Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy? Expert Opin. Invest. Drugs. 2019;28(2):107–112. doi: 10.1080/13543784.2019.1555239. [DOI] [PubMed] [Google Scholar]
Yeeravalli R. Das A. Molecular mediators of breast cancer metastasis. Hematology/Oncology and Stem. Cell Ther. 2021;14(4):275–289. doi: 10.1016/j.hemonc.2021.02.002. [DOI] [PubMed] [Google Scholar]
Burcu B. Ertas I. Sener A. Demircioglu Z. G. Cerekci E. Kaya C. Retrospective Analysis of Parameters Affecting Metastatic Breast Cancer. Sisli Etfal Hastan Tip Bull. 2023;57(4):479–484. doi: 10.14744/SEMB.2023.94803. https://dx.doi.org/10.14744/semb.2023.94803 [DOI] [PMC free article] [PubMed] [Google Scholar]
Guo L. Kong D. Liu J. Zhan L. Luo L. Zheng W. Zheng Q. Chen C. Sun S. Breast cancer heterogeneity and its implication in personalized precision therapy. Exp. Hematol. Oncol. 2023;12(1):3. doi: 10.1186/s40164-022-00363-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Liu T. Song S. Wang X. Hao J. Small-molecule inhibitors of breast cancer-related targets: Potential therapeutic agents for breast cancer. Eur. J. Med. Chem. 2021;210:112954. doi: 10.1016/j.ejmech.2020.112954. [DOI] [PubMed] [Google Scholar]
Ajayi E. D. Elazazy M. Abouzid K. Ali H. I. Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration. Eur. J. Med. Chem. 2026;301:118219. doi: 10.1016/j.ejmech.2025.118219. [DOI] [PubMed] [Google Scholar]
Mo F. Pellerino A. Soffietti R. Rudà R. Blood-Brain Barrier in Brain Tumors: Biology and Clinical Relevance. Int. J. Mol. Sci. 2021;22(23):12654. doi: 10.3390/ijms222312654. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lockman P. R. Mittapalli R. K. Taskar K. S. Rudraraju V. Gril B. Bohn K. A. Adkins C. E. Roberts A. Thorsheim H. R. Gaasch J. A. Huang S. Palmieri D. Steeg P. S. Smith Q. R. Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer. Clin. Cancer Res. 2010;16(23):5664–5678. doi: 10.1158/1078-0432.CCR-10-1564. https://dx.doi.org/10.1158/1078-0432.Ccr-10-1564 [DOI] [PMC free article] [PubMed] [Google Scholar]
Riecke K. Müller V. Neunhöffer T. Park-Simon T. W. Weide R. Polasik A. Schmidt M. Puppe J. Mundhenke C. Lübbe K. Hesse T. Thill M. Wuerstlein R. Denkert C. Decker T. Fehm T. Nekljudova V. Rey J. Loibl S. Laakmann E. Witzel I. Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry. ESMO Open. 2023;8(3):101213. doi: 10.1016/j.esmoop.2023.101213. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zimmer A. S. Van Swearingen A. E. D. Anders C. K. HER2-positive breast cancer brain metastasis: A new and exciting landscape. Cancer Rep. 2022;5(4):e1274. doi: 10.1002/cnr2.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yu Y. Huang K. Lin Y. Zhang J. Song C. Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis. Cancer Med. 2023;12(14):15090–15100. doi: 10.1002/cam4.6180. [DOI] [PMC free article] [PubMed] [Google Scholar]
Guglielmi G. Zamagni C. Del Re M. Danesi R. Fogli S. Targeting HER2 in breast cancer with brain metastases: A pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments. Eur. J. Pharmacol. 2024;985:177076. doi: 10.1016/j.ejphar.2024.177076. [DOI] [PubMed] [Google Scholar]
Cornelissen F. M. G. Markert G. Deutsch G. Antonara M. Faaij N. Bartelink I. Noske D. Vandertop W. P. Bender A. Westerman B. A. Explaining Blood–Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms. J. Med. Chem. 2023;66(11):7253–7267. doi: 10.1021/acs.jmedchem.2c01824. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang H. Zhao Y. Wang Y. Ma X. Ling J. Zeng X. Li Z. Liao G. Triple-Negative Breast Cancer Brain Metastasis: A Comprehensive Review of Epidemiology, Molecular Pathobiology, and Therapeutic Frontiers. Cancers. 2026;18(7):1179. doi: 10.3390/cancers18071179. [DOI] [PMC free article] [PubMed] [Google Scholar]
Liu Z. Li M. Zhao Z. Liu A. Sun P. Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases. Front. Oncol. 2024;14:1439984. doi: 10.3389/fonc.2024.1439984. [DOI] [PMC free article] [PubMed] [Google Scholar]
Brognard J. Hunter T. Protein kinase signaling networks in cancer. Curr. Opin. Genet. Dev. 2011;21(1):4–11. doi: 10.1016/j.gde.2010.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
Du Z. Lovly C. M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer. 2018;17(1):58. doi: 10.1186/s12943-018-0782-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cheng H. C. Qi R. Z. Paudel H. Zhu H. J. Regulation and function of protein kinases and phosphatases. Enzym. Res. 2011;2011:794089. doi: 10.4061/2011/794089. [DOI] [PMC free article] [PubMed] [Google Scholar]
Singh S. S. and Jois S. D., Chapter One - Homo- and Heterodimerization of Proteins in Cell Signaling: Inhibition and Drug Design, in Advances in Protein Chemistry and Structural Biology, ed. R. Donev, Academic Press, 2018, pp. 1–59 [DOI] [PMC free article] [PubMed] [Google Scholar]
Lemmon M. A. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–1134. doi: 10.1016/j.cell.2010.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
Haubrich J. Zwier J. M. Charrier-Savournin F. Prézeau L. Pin J. P. Different EGF-induced receptor dimer conformations for signaling and internalization. FASEB J. 2024;38(1):e23356. doi: 10.1096/fj.202301209R. [DOI] [PubMed] [Google Scholar]
Zhang Y. Alexander P. B. Wang X. F. TGF-β Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harbor Perspect. Biol. 2017;9(4):a022145. doi: 10.1101/cshperspect.a022145. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bansal I. Pandey A. K. Ruwali M. Small-molecule inhibitors of kinases in breast cancer therapy: recent advances, opportunities, and challenges. Front. Pharmacol. 2023;14:1244597. doi: 10.3389/fphar.2023.1244597. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gross S. Rahal R. Stransky N. Lengauer C. Hoeflich K. P. Targeting cancer with kinase inhibitors. J. Clin. Invest. 2015;125(5):1780–1789. doi: 10.1172/JCI76094. https://dx.doi.org/10.1172/jci76094 [DOI] [PMC free article] [PubMed] [Google Scholar]
Bhullar K. S. Lagarón N. O. McGowan E. M. Parmar I. Jha A. Hubbard B. P. Rupasinghe H. P. V. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer. 2018;17(1):48. doi: 10.1186/s12943-018-0804-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Arter C. Trask L. Ward S. Yeoh S. Bayliss R. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. J. Biol. Chem. 2022;298(8):102247. doi: 10.1016/j.jbc.2022.102247. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lee P. Y. Yeoh Y. Low T. Y. A recent update on small-molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry-based proteomic analysis. FASEB J. 2023;290(11):2845–2864. doi: 10.1111/febs.16442. [DOI] [PubMed] [Google Scholar]
Vijayan R. S. K. He P. Modi V. Duong-Ly K. C. Ma H. Peterson J. R. Dunbrack Jr. R. L. Levy R. M. Conformational Analysis of the DFG-Out Kinase Motif and Biochemical Profiling of Structurally Validated Type II Inhibitors. J. Med. Chem. 2015;58(1):466–479. doi: 10.1021/jm501603h. [DOI] [PMC free article] [PubMed] [Google Scholar]
Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 2016;103:26–48. doi: 10.1016/j.phrs.2015.10.021. [DOI] [PubMed] [Google Scholar]
Martinez R., Defnet A. and Shapiro P., Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors, in Next Generation Kinase Inhibitors: Moving beyond the ATP Binding/Catalytic Sites, ed. P. Shapiro, Springer International Publishing, Cham, 2020, pp. 29–59 [Google Scholar]
Łukasik P. Baranowska-Bosiacka I. Kulczycka K. Gutowska I. Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action. Int. J. Mol. Sci. 2021;22(6):2806. doi: 10.3390/ijms22062806. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gavrin L. K. Saiah E. Approaches to discover non-ATP site kinase inhibitors. MedChemComm. 2013;4(1):41–51. doi: 10.1039/C2MD20180A. [DOI] [Google Scholar]
Lee P. Y. Yeoh Y. Low T. Y. A recent update on small-molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry-based proteomic analysis. FEBS J. 2023;290(11):2845–2864. doi: 10.1111/febs.16442. [DOI] [PubMed] [Google Scholar]
Lee S. Kim J. Jo J. Chang J. W. Sim J. Yun H. Recent advances in development of hetero-bivalent kinase inhibitors. Eur. J. Med. Chem. 2021;216:113318. doi: 10.1016/j.ejmech.2021.113318. [DOI] [PubMed] [Google Scholar]
Zhao Z. Liu Q. Bliven S. Xie L. Bourne P. E. Determining Cysteines Available for Covalent Inhibition Across the Human Kinome. J. Med. Chem. 2017;60(7):2879–2889. doi: 10.1021/acs.jmedchem.6b01815. [DOI] [PMC free article] [PubMed] [Google Scholar]
Eshaq A. M. Flanagan T. W. Hassan S. Y. Al Asheikh S. A. Al-Amoudi W. A. Santourlidis S. Hassan S. L. Alamodi M. O. Bendhack M. L. Alamodi M. O. Haikel Y. Megahed M. Hassan M. Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance. Cancers. 2024;16(15):2754. doi: 10.3390/cancers16152754. [DOI] [PMC free article] [PubMed] [Google Scholar]
Qi Y. Deng S. M. Wang K. S. Receptor tyrosine kinases in breast cancer treatment: unraveling the potential. Am. J. Cancer Res. 2024;14(9):4172–4196. doi: 10.62347/KIVS3169. https://dx.doi.org/10.62347/kivs3169 [DOI] [PMC free article] [PubMed] [Google Scholar]
Maruyama I. N. Mechanisms of activation of receptor tyrosine kinases: monomers or dimers. Cells. 2014;3(2):304–330. doi: 10.3390/cells3020304. [DOI] [PMC free article] [PubMed] [Google Scholar]
Montor W. R. Salas A. R. O. S. E. Melo F. H. Md. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol. Cancer. 2018;17(1):55. doi: 10.1186/s12943-018-0792-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hubbard S. R. Miller W. T. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol. 2007;19(2):117–123. doi: 10.1016/j.ceb.2007.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
Aref M. M. A. Abdallah A. E. Dahab M. A. Mohamed A. A. Celik I. Bawazir W. A. Mansoure A. A. Alnami A. T. Abdelhamed M. N. El-Zahabi M. A. Design, synthesis, anticancer evaluation, biological screening, and computational study of novel 6,7-dimethoxyquinazoline derivatives as VEGFR-2 inhibitors and apoptotic inducers. Eur. J. Med. Chem. 2026;301:118187. doi: 10.1016/j.ejmech.2025.118187. [DOI] [PubMed] [Google Scholar]
Xuhong J. C. Qi X. W. Zhang Y. Jiang J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am. J. Cancer Res. 2019;9(10):2103–2119. [PMC free article] [PubMed] [Google Scholar]
Sun K. Wang X. Zhang H. Lin G. Jiang R. Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer. Cancer Control. 2024;31:10732748241278039. doi: 10.1177/10732748241278039. [DOI] [PMC free article] [PubMed] [Google Scholar]
Shyam S. S. Sharma U. C. Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduction Targeted Ther. 2023;8(1):262. doi: 10.1038/s41392-023-01469-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Shyam Sunder S. Sharma U. C. Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduction Targeted Ther. 2023;8(1):262. doi: 10.1038/s41392-023-01469-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Green J. R. Mahalingaiah P. K. S. Gopalakrishnan S. M. Liguori M. J. Mittelstadt S. W. Blomme E. A. G. Van Vleet T. R. Off-target pharmacological activity at various kinases: Potential functional and pathological side effects. J. Pharmacol. Toxicol. Methods. 2023;123:107468. doi: 10.1016/j.vascn.2023.107468. [DOI] [PubMed] [Google Scholar]
Jin Y. Xu Z. Yan H. He Q. Yang X. Luo P. A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors. Front. Pharmacol. 2020;11:891. doi: 10.3389/fphar.2020.00891. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li J. Gong C. Zhou H. Liu J. Xia X. Ha W. Jiang Y. Liu Q. Xiong H. Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives. Int. J. Mol. Sci. 2024;25(10):5489. doi: 10.3390/ijms25105489. [DOI] [PMC free article] [PubMed] [Google Scholar]
Shrestha S. Bendzunas G. Kannan N. Protein kinase inhibitor selectivity “hinges” on evolution. Structure. 2022;30(12):1561–1563. doi: 10.1016/j.str.2022.11.004. [DOI] [PubMed] [Google Scholar]
Li Y. Fu R. Jiang T. Duan D. Wu Y. Li C. Li Z. Ni R. Li L. Liu Y. Mechanism of Lethal Skin Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors and Related Treatment Strategies. Front. Oncol. 2022;12:804212. doi: 10.3389/fonc.2022.804212. [DOI] [PMC free article] [PubMed] [Google Scholar]
Dan H. Jiang Q. Jia X. Qi G. Zong D. Li Z. Dermatologic toxicities in epidermal growth factor receptor: a comprehensive pharmacovigilance study from 2013 to 2023. Front. Med. 2024:10–2023. doi: 10.3389/fmed.2023.1283807. [DOI] [PMC free article] [PubMed] [Google Scholar]
Raja S. R. Khan J. Ibahim M. J. Muhamad M. Bowen J. Wan M. Zain W. N. I. Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review. BioMed Res. Int. 2022;2022:4165808. doi: 10.1155/2022/4165808. [DOI] [PMC free article] [PubMed] [Google Scholar]
Arter C. Trask L. Ward S. Yeoh S. Bayliss R. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. J. Biol. Chem. 2022;298(8) doi: 10.1016/j.jbc.2022.102247. [DOI] [PMC free article] [PubMed] [Google Scholar]
Xing L. Klug-Mcleod J. Rai B. Lunney E. A. Kinase hinge binding scaffolds and their hydrogen bond patterns. Bioorg. Med. Chem. 2015;23(19):6520–6527. doi: 10.1016/j.bmc.2015.08.006. [DOI] [PubMed] [Google Scholar]
Brauer N. R. Kempen A. L. Hernandez D. Sintim H. O. Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors. Eur. J. Med. Chem. 2024;275:116540. doi: 10.1016/j.ejmech.2024.116540. [DOI] [PMC free article] [PubMed] [Google Scholar]
Reinecke M. Brear P. Vornholz L. Berger B.-T. Seefried F. Wilhelm S. Samaras P. Gyenis L. Litchfield D. W. Médard G. Müller S. Ruland J. Hyvönen M. Wilhelm M. Kuster B. Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors. Nat. Chem. Biol. 2024;20(5):577–585. doi: 10.1038/s41589-023-01459-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Reynders M. Chaikuad A. Berger B. T. Bauer K. Koch P. Laufer S. Knapp S. Trauner D. Controlling the Covalent Reactivity of a Kinase Inhibitor with Light. Angew. Chem., Int. Ed. Engl. 2021;60(37):20178–20183. doi: 10.1002/anie.202103767. [DOI] [PMC free article] [PubMed] [Google Scholar]
Montaño J. L. Wang B. J. Volk R. F. Warrington S. E. Garda V. G. Hofmann K. L. Chen L. C. Zaro B. W. Improved Electrophile Design for Exquisite Covalent Molecule Selectivity. ACS Chem. Biol. 2022;17(6):1440–1449. doi: 10.1021/acschembio.1c00980. [DOI] [PubMed] [Google Scholar]
Békés M. Langley D. R. Crews C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discovery. 2022;21(3):181–200. doi: 10.1038/s41573-021-00371-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yu F. Cai M. Shao L. Zhang J. Targeting Protein Kinases Degradation by PROTACs. Front. Chem. 2021:9–2021. doi: 10.3389/fchem.2021.679120. [DOI] [PMC free article] [PubMed] [Google Scholar]
Broekman F. Giovannetti E. Peters G. J. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J. Clin. Oncol. 2011;2(2):80–93. doi: 10.5306/wjco.v2.i2.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
Knight Z. A. Lin H. Shokat K. M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer. 2010;10(2):130–137. doi: 10.1038/nrc2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
Sirhan Z. Thyagarajan A. Sahu R. P. The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer. Mil. Med. Res. 2022;9(1):39. doi: 10.1186/s40779-022-00401-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gutierrez C. Schiff R. HER2: biology, detection, and clinical implications. Arch. Pathol. Lab. Med. 2011;135(1):55–62. doi: 10.5858/2010-0454-rar.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jaradat S. K. Ayoub N. M. Al Sharie A. H. Aldaod J. M. Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer. Technol. Cancer Res. Treat. 2024;23:15330338241234780. doi: 10.1177/15330338241234780. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ou X. Gao G. Habaz I. A. Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm. 2024;5(9):e694. doi: 10.1002/mco2.694. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang Y. Li S. Wang Y. Zhao Y. Li Q. Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective. Signal Transduction Targeted Ther. 2022;7(1):329. doi: 10.1038/s41392-022-01168-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Marín A. Mamun A. A. Patel H. Akamatsu H. Ye D. Sudhan D. R. Eli L. Marcelain K. Brown B. P. Meiler J. Arteaga C. L. Hanker A. B. Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer. Cancer Res. 2023;83(18):3145–3158. doi: 10.1158/0008-5472.CAN-22-3617. https://dx.doi.org/10.1158/0008-5472.Can-22-3617 [DOI] [PMC free article] [PubMed] [Google Scholar]
Lu J. Zhou K. Yin X. Xu H. Ma B. Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer. Comput. Biol. Chem. 2019;78:290–296. doi: 10.1016/j.compbiolchem.2018.12.007. [DOI] [PubMed] [Google Scholar]
Kumar N. Ehsan S. Banerjee S. Fernandez P. C. Lhuilier I. Neuner J. Friebel-Klingner T. Fayanju O. M. Nair B. Niinuma S. A. Nampoothiri S. McCarthy A. M. The unique risk factor profile of triple-negative breast cancer: a comprehensive meta-analysis. J. Natl. Cancer Inst. 2024;116(8):1210–1219. doi: 10.1093/jnci/djae056. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hirotsu Y. Nakagomi H. Amemiya K. Oyama T. Inoue M. Mochizuki H. Omata M. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med. Oncol. 2016;34(1):3. doi: 10.1007/s12032-016-0857-2. [DOI] [PubMed] [Google Scholar]
Xu X. De A. C. Burke K. A. Nardone A. Hu H. Qin L. Veeraraghavan J. Sethunath V. Heiser L. M. Wang N. Ng C. K. Y. Chen E. S. Renwick A. Wang T. Nanda S. Shea M. Mitchell T. Rajendran M. Waters I. Zabransky D. J. Scott K. L. Gutierrez C. Nagi C. Geyer F. C. Chamness G. C. Park B. H. Shaw C. A. Hilsenbeck S. G. Rimawi M. F. Gray J. W. Weigelt B. Reis-Filho J. S. Osborne C. K. Schiff R. HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2(+) Breast Cancer. Clin. Cancer Res. 2017;23(17):5123–5134. doi: 10.1158/1078-0432.CCR-16-2191. https://dx.doi.org/10.1158/1078-0432.Ccr-16-2191 [DOI] [PMC free article] [PubMed] [Google Scholar]
Wu Z. Wang J. You F. Li X. Xiao C. The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer. Front. Pharmacol. 2023;14 doi: 10.3389/fphar.2023.1142087. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chumsri S. Sperinde J. Liu H. Gligorov J. Spano J. P. Antoine M. Moreno Aspitia A. Tan W. Winslow J. Petropoulos C. J. Chenna A. Bates M. Weidler J. M. Huang W. Dueck A. Perez E. A. High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance) Clin. Cancer Res. 2018;24(13):3053–3058. doi: 10.1158/1078-0432.CCR-17-1864. https://dx.doi.org/10.1158/1078-0432.Ccr-17-1864 [DOI] [PMC free article] [PubMed] [Google Scholar]
Jaradat S. K. Ayoub N. M. Al Sharie A. H. Aldaod J. M. Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer. Technol. Cancer Res. Treat. 2024;23:15330338241234780. doi: 10.1177/15330338241234780. [DOI] [PMC free article] [PubMed] [Google Scholar]
Blangé D. Stroes C. I. Derks S. Bijlsma M. F. van Laarhoven H. W. M. Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review. Cancer Treat. Rev. 2022;108:102418. doi: 10.1016/j.ctrv.2022.102418. [DOI] [PubMed] [Google Scholar]
Ahmed M. E. David A. G. An overview of resistance to Human epidermal growth factor receptor 2 (Her2) targeted therapies in breast cancer. Cancer Drug Resist. 2022;5(2):472–486. doi: 10.20517/cdr.2022.09. [DOI] [PMC free article] [PubMed] [Google Scholar]
Stuhlmiller Timothy J. Miller S. M. Zawistowski Jon S. Nakamura K. Beltran Adriana S. Duncan J. S. Angus Steven P. Collins Kyla A. L. Granger Deborah A. Reuther Rachel A. Graves Lee M. Gomez Shawn M. Kuan P.-F. Parker J. S. Chen X. Sciaky N. Carey Lisa A. Earp H. S. Jin J. Johnson Gary L. Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains. Cell Rep. 2015;11(3):390–404. doi: 10.1016/j.celrep.2015.03.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
Duncan J. S. Whittle Martin C. Nakamura K. Abell Amy N. Midland Alicia A. Zawistowski Jon S. Johnson Nancy L. Granger Deborah A. Jordan Nicole V. Darr David B. Usary J. Kuan P.-F. Smalley David M. Major B. He X. Hoadley Katherine A. Zhou B. Sharpless Norman E. Perou Charles M. Kim W. Y. Gomez Shawn M. Chen X. Jin J. Frye Stephen V. Earp H. S. Graves Lee M. Johnson G. L. Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer. Cell. 2012;149(2):307–321. doi: 10.1016/j.cell.2012.02.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
Johnson G. L. Stuhlmiller T. J. Angus S. P. Zawistowski J. S. Graves L. M. Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF–MEK–ERK Pathway in Cancer. Clin. Cancer Res. 2014;20(10):2516–2522. doi: 10.1158/1078-0432.CCR-13-1081. https://dx.doi.org/10.1158/1078-0432.Ccr-13-1081 [DOI] [PMC free article] [PubMed] [Google Scholar]
Li X. Huang X. Chang M. Lin R. Zhang J. Lu Y. Updates on altered signaling pathways in tumor drug resistance. Visualized Cancer Med. 2024;5:6. doi: 10.1051/vcm/2024007. [DOI] [Google Scholar]
Young Hee C. Ai-Ming Y. ABC Transporters in Multidrug Resistance and Pharmacokinetics, and Strategies for Drug Development. Curr. Pharm. Des. 2014;20(5):793–807. doi: 10.2174/138161282005140214165212. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang Y. Tu M.-J. Yu A.-M. Efflux ABC transporters in drug disposition and their posttranscriptional gene regulation by microRNAs. Front. Pharmacol. 2024;15 doi: 10.3389/fphar.2024.1423416. [DOI] [PMC free article] [PubMed] [Google Scholar]
He J. Qiu Z. Fan J. Xie X. Sheng Q. Sui X. Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies. Signal Transduction Targeted Ther. 2024;9(1):209. doi: 10.1038/s41392-024-01891-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bhat G. R. Sethi I. Sadida H. Q. Rah B. Mir R. Algehainy N. Albalawi I. A. Masoodi T. Subbaraj G. K. Jamal F. Singh M. Kumar R. Macha M. A. Uddin S. Akil A. S. A.-S. Haris M. Bhat A. A. Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev. 2024;43(1):197–228. doi: 10.1007/s10555-024-10172-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
Liu S. Jiang A. Tang F. Duan M. Li B. Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment. Mol. Cancer. 2025;24(1):150. doi: 10.1186/s12943-025-02323-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Emmons M. F. Faião-Flores F. Smalley K. S. M. The role of phenotypic plasticity in the escape of cancer cells from targeted therapy. Biochem. Pharmacol. 2016;122:1–9. doi: 10.1016/j.bcp.2016.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
Baghban R. Roshangar L. Jahanban-Esfahlan R. Seidi K. Ebrahimi-Kalan A. Jaymand M. Kolahian S. Javaheri T. Zare P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020;18(1):59. doi: 10.1186/s12964-020-0530-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Khalaf K. Hana D. Chou J. T.-T. Singh C. Mackiewicz A. Kaczmarek M. Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front. Immunol. 2021;12 doi: 10.3389/fimmu.2021.656364. [DOI] [PMC free article] [PubMed] [Google Scholar]
Harry J. A. Ormiston M. L. Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer. Front. Oncol. 2021;11 doi: 10.3389/fonc.2021.772305. [DOI] [PMC free article] [PubMed] [Google Scholar]
Murphy J. M. Rodriguez Y. A. R. Jeong K. Ahn E. E. Lim S. S. Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp. Mol. Med. 2020;52(6):877–886. doi: 10.1038/s12276-020-0447-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Korkaya H. Liu S. Wicha M. S. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest. 2011;121(10):3804–3809. doi: 10.1172/JCI57099. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schlam I. Swain S. M. HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now. npj Breast Cancer. 2021;7(1):56. doi: 10.1038/s41523-021-00265-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cremers C. G. Nguyen L. K. Network rewiring, adaptive resistance and combating strategies in breast cancer. Cancer Drug Resist. 2019;2(4):1106–1126. doi: 10.20517/cdr.2019.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
Iancu G. Serban D. Badiu C. D. Tanasescu C. Tudosie M. S. Tudor C. Costea D. O. Zgura A. Iancu R. Vasile D. Tyrosine kinase inhibitors in breast cancer (Review) Exp. Ther. Med. 2022;23(2):114. doi: 10.3892/etm.2021.11037. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ou X. Gao G. Habaz I. A. Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm. 2024;5(9):e694. doi: 10.1002/mco2.694. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang B. Wu H. Hu C. Wang H. Liu J. Wang W. Liu Q. An overview of kinase downregulators and recent advances in discovery approaches. Signal Transduction Targeted Ther. 2021;6(1):423. doi: 10.1038/s41392-021-00826-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
De S. K., An Overview of Protein Kinase Inhibitors, Drug Design and Discovery: Inhibitors of Mitogen-Activated Protein Kinases, Springer Nature Switzerland, Cham, 2024, pp. 1–42 [Google Scholar]
Olson D. Taylor J. Willis K. Hensley K. Allred S. Zaval M. Farr L. Thurman R. Jain N. Hein R. Ulrich M. Peterson S. Kulukian A. HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer. Cancer Res. Commun. 2023;3(9):1927–1939. doi: 10.1158/2767-9764.CRC-23-0302. https://dx.doi.org/10.1158/2767-9764.Crc-23-0302 [DOI] [PMC free article] [PubMed] [Google Scholar]
Reema W.-A. Bolin L. Ann D. T. Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem. Cancer Drug Resist. 2020;3(2):179–198. doi: 10.20517/cdr.2019.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
Huang F. Han X. Xiao X. Zhou J. Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development. Molecules. 2022;27(22):7728. doi: 10.3390/molecules27227728. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zhao Z. Bourne P. E. Exploring Extended Warheads toward Developing Cysteine-Targeted Covalent Kinase Inhibitors. J. Chem. Inf. Model. 2024;64(24):9517–9527. doi: 10.1021/acs.jcim.4c00890. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bálint D. Póti Á. L. Alexa A. Sok P. Albert K. Torda L. Földesi-Nagy D. Csókás D. Turczel G. Imre T. Szarka E. Fekete F. Bento I. Bojtár M. Palkó R. Szabó P. Monostory K. Pápai I. Soós T. Reményi A. Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads. Nat. Commun. 2024;15(1):8606. doi: 10.1038/s41467-024-52573-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wu P. Clausen M. H. Nielsen T. E. Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015;156:59–68. doi: 10.1016/j.pharmthera.2015.10.002. [DOI] [PubMed] [Google Scholar]
Tomuleasa C. Tigu A.-B. Munteanu R. Moldovan C.-S. Kegyes D. Onaciu A. Gulei D. Ghiaur G. Einsele H. Croce C. M. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduction Targeted Ther. 2024;9(1):201. doi: 10.1038/s41392-024-01899-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
Luan Y. Li J. Bernatchez J. A. Li R. Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. J. Med. Chem. 2019;62(7):3171–3183. doi: 10.1021/acs.jmedchem.8b00189. [DOI] [PubMed] [Google Scholar]
Biersack B. Polat S. Höpfner M. Anticancer properties of chimeric HDAC and kinase inhibitors. Semin. Cancer Biol. 2022;83:472–486. doi: 10.1016/j.semcancer.2020.11.005. [DOI] [PubMed] [Google Scholar]
Bass A. K. A. El-Zoghbi M. S. Nageeb E.-S. M. Mohamed M. F. A. Badr M. Abuo-Rahma G. E.-D. A. Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors. Eur. J. Med. Chem. 2021;209:112904. doi: 10.1016/j.ejmech.2020.112904. [DOI] [PubMed] [Google Scholar]
Szumilak M. Wiktorowska-Owczarek A. Stanczak A. Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance? Molecules. 2021;26(9):2601. doi: 10.3390/molecules26092601. [DOI] [PMC free article] [PubMed] [Google Scholar]
He M. Cao C. Ni Z. Liu Y. Song P. Hao S. He Y. Sun X. Rao Y. PROTACs: great opportunities for academia and industry (an update from 2020 to 2021) Signal Transduction Targeted Ther. 2022;7(1):181. doi: 10.1038/s41392-022-00999-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Faryal B. Ul Abideen Z. Irfan M. Ahmed H. Jalilov F. Abduraximova L. Ashraf G. A. Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms. Biomolecules. 2026;16(2):325. doi: 10.3390/biom16020325. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang Z. Li Z. Högström J. Inuzuka H. Jing R. Yan P. Hou T. Qi Y. Huang D. Wang J. Wu T. Shi X. Liu B. Muranen T. Zhang D. Wei W. Dual membrane receptor degradation via folate receptor targeting chimera. Nat. Commun. 2025;16(1):8804. doi: 10.1038/s41467-025-63882-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gumusay O., Vitiello P. P., Wabl C., Corcoran R. B., Bardelli A. and Rugo H. S., Strategic Combinations to Prevent and Overcome Resistance to Targeted Therapies in Oncology, American Society of Clinical Oncology Educational Book, 2020, vol. 40, pp. e292–e308, 10.1200/edbk_280845. PubMed PMID: 32453634 [DOI] [PubMed] [Google Scholar]
Rexer B. N. Arteaga C. L. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit. Rev. Oncog. 2012;17(1):1–16. doi: 10.1615/CritRevOncog.v17.i1.20. https://dx.doi.org/10.1615/critrevoncog.v17.i1.20 [DOI] [PMC free article] [PubMed] [Google Scholar]
Wu X. Yang H. Yu X. Qin J.-J. Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies. Front. Pharmacol. 2022;13 doi: 10.3389/fphar.2022.1012552. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nikanjam M. Liu S. Yang J. Kurzrock R. Dosing Three-Drug Combinations That Include Targeted Anti-Cancer Agents: Analysis of 37,763 Patients. Oncologist. 2017;22(5):576–584. doi: 10.1634/theoncologist.2016-0357. [DOI] [PMC free article] [PubMed] [Google Scholar]
Rosell R. Karachaliou N. Morales-Espinosa D. Costa C. Molina M. A. Sansano I. Gasco A. Viteri S. Massuti B. Wei J. Cao M. G. Bueno A. M. Adaptive resistance to targeted therapies in cancer. Transl. Lung Cancer Res. 2013;2(3):152–159. doi: 10.3978/j.issn.2218-6751.2012.12.08. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schlam I. Tarantino P. Tolaney S. M. Overcoming Resistance to HER2-Directed Therapies in Breast Cancer. Cancers. 2022;14(16):3996. doi: 10.3390/cancers14163996. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tan Y. Q. Chiou Y.-S. Guo H. Zhang S. Huang X. Dukanya D. Kumar A. M. Basappa S. Liu S. Zhu T. Basappa B. Pandey V. Lobie P. E. Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer. npj Precis. Oncol. 2024;8(1):8. doi: 10.1038/s41698-023-00489-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Butti R. Das S. Gunasekaran V. P. Yadav A. S. Kumar D. Kundu G. C. Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges. Mol. Cancer. 2018;17(1):34. doi: 10.1186/s12943-018-0797-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mizuno T. Sakai T. Tanabe K. Umemura T. Goto N. Ohtsu F. Visualization of Kinase Inhibition-Related Adverse Events Using the Japanese Adverse Drug Event Report Database. Drugs Real World Outcomes. 2021;8(2):197–206. doi: 10.1007/s40801-021-00235-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li Y. Fu R. Jiang T. Duan D. Wu Y. Li C. Li Z. Ni R. Li L. Liu Y. Mechanism of Lethal Skin Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors and Related Treatment Strategies. Front. Oncol. 2022;12 doi: 10.3389/fonc.2022.804212. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tao G. Chityala P. K. Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management. Toxicol. Res. 2021;10(3):476–486. doi: 10.1093/toxres/tfab026. [DOI] [PMC free article] [PubMed] [Google Scholar]
Recuero J. K. Fitz J. R. Pereira A. A. Bonamigo R. R. EGFR inhibitors: clinical aspects, risk factors and biomarkers for acneiform eruptions and other mucosal and cutaneous adverse effects. An. Bras. Dermatol. 2023;98(4):429–439. doi: 10.1016/j.abd.2022.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
Le Du F. Diéras V. Curigliano G. The role of tyrosine kinase inhibitors in the treatment of HER2+ metastatic breast cancer. Eur. J. Cancer. 2021;154:175–189. doi: 10.1016/j.ejca.2021.06.026. [DOI] [PubMed] [Google Scholar]
Diabetes NIo, Digestive, Diseases K. Lapatinib, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2019, Available from: https://www.ncbi.nlm.nih.gov/books/NBK547971/ [Google Scholar]
Diabetes NIo, Digestive, Diseases K. Tucatinib, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2023, Available from: https://www.ncbi.nlm.nih.gov/books/NBK595112/ [Google Scholar]
Towles J. K. Clark R. N. Wahlin M. D. Uttamsingh V. Rettie A. E. Jackson K. D. Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib. Drug Metab. Dispos. 2016;44(10):1584–1597. doi: 10.1124/dmd.116.070839. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hardy K. D. Wahlin M. D. Papageorgiou I. Unadkat J. D. Rettie A. E. Nelson S. D. Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab. Dispos. 2014;42(1):162–171. doi: 10.1124/dmd.113.054817. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kulukian A. Lee P. Taylor J. Rosler R. de Vries P. Watson D. Forero-Torres A. Peterson S. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol. Cancer Ther. 2020;19(4):976–987. doi: 10.1158/1535-7163.MCT-19-0873. https://dx.doi.org/10.1158/1535-7163.Mct-19-0873 [DOI] [PubMed] [Google Scholar]
Saran C. Sundqvist L. Ho H. Niskanen J. Honkakoski P. Brouwer K. L. R. Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors. J. Pharmacol. Exp. Ther. 2022;380(2):114–125. doi: 10.1124/jpet.121.000828. [DOI] [PMC free article] [PubMed] [Google Scholar]
Saran C. Brouwer K. L. R. Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity. Toxicol. Pathol. 2023;51(7–8):405–413. doi: 10.1177/01926233231212255. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen M. Borlak J. Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1):388–396. doi: 10.1002/hep.26208. [DOI] [PubMed] [Google Scholar]
McEuen K. Borlak J. Tong W. Chen M. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury. Int. J. Mol. Sci. 2017;18(7):1335. doi: 10.3390/ijms18071335. [DOI] [PMC free article] [PubMed] [Google Scholar]
Viganò M. La Milia M. Grassini M. V. Pugliese N. De Giorgio M. Fagiuoli S. Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer. Cancers. 2023;15(6):1766. doi: 10.3390/cancers15061766. [DOI] [PMC free article] [PubMed] [Google Scholar]
Di Martino R. M. C. Maxwell B. D. Pirali T. Deuterium in drug discovery: progress, opportunities and challenges. Nat. Rev. Drug Discovery. 2023;22(7):562–584. doi: 10.1038/s41573-023-00703-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Xu V. Ahmed B. Boleslav B. Mager D. E. Sparreboom A. Sprowl J. A. Huang K. M. Insights and perspectives into the etiology of TKI-induced cardiotoxicity. ASPET Discovery. 2026;2:100025. doi: 10.1016/j.aspetd.2026.100025. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bæk Møller N. Budolfsen C. Grimm D. Krüger M. Infanger M. Wehland M. Magnusson N. E. Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment. Int. J. Mol. Sci. 2019;20(19):4712. doi: 10.3390/ijms20194712. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jha P. K. Nakano T. Itto L. Y. U. Barbeiro M. C. Lupieri A. Aikawa E. Aikawa M. Vascular inflammation in chronic kidney disease: the role of uremic toxins in macrophage activation. Front. Cardiovasc. Med. 2025;12 doi: 10.3389/fcvm.2025.1574489. [DOI] [PMC free article] [PubMed] [Google Scholar]
Baldi S. Long N. Ma S. Liu L. Al-Danakh A. Yang Q. Deng X. Xie J. Tang H. Advancements in Protein Kinase Inhibitors: From Discovery to Clinical Applications. Research. 2025;8:0747. doi: 10.34133/research.0747. [DOI] [PMC free article] [PubMed] [Google Scholar]
Xerxa E. Laufkötter O. Bajorath J. Systematic Analysis of Covalent and Allosteric Protein Kinase Inhibitors. Molecules. 2023;28(15):5805. doi: 10.3390/molecules28155805. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang X. DeFilippis R. A. Yan W. Shah N. P. Li H.-y. Overcoming Secondary Mutations of Type II Kinase Inhibitors. J. Med. Chem. 2024;67(12):9776–9788. doi: 10.1021/acs.jmedchem.3c01629. [DOI] [PMC free article] [PubMed] [Google Scholar]
Treiber D. K. Shah Neil P. Ins and Outs of Kinase DFG Motifs. Chem. Biol. 2013;20(6):745–746. doi: 10.1016/j.chembiol.2013.06.001. [DOI] [PubMed] [Google Scholar]
Bradshaw J. M. McFarland J. M. Paavilainen V. O. Bisconte A. Tam D. Phan V. T. Romanov S. Finkle D. Shu J. Patel V. Ton T. Li X. Loughhead D. G. Nunn P. A. Karr D. E. Gerritsen M. E. Funk J. O. Owens T. D. Verner E. Brameld K. A. Hill R. J. Goldstein D. M. Taunton J. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 2015;11(7):525–531. doi: 10.1038/nchembio.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kenneth K. H. David M. T. Adam R. R. Michelle R. A. Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery. Curr. Top. Med. Chem. 2017;17(1):4–15. doi: 10.2174/1568026616666160719163839. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lai A. C. Crews C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discovery. 2017;16(2):101–114. doi: 10.1038/nrd.2016.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kossakowski K. Cherniienko A. Zaprutko L. Pawełczyk A. FDA-approved kinase inhibitors in PROTAC design, development and synthesis. J. Enzyme Inhib. Med. Chem. 2025;40(1):2542357. doi: 10.1080/14756366.2025.2542357. [DOI] [PMC free article] [PubMed] [Google Scholar]
Steelman L. S. Chappell W. H. Abrams S. L. Kempf R. C. Long J. Laidler P. Mijatovic S. Maksimovic-Ivanic D. Stivala F. Mazzarino M. C. Donia M. Fagone P. Malaponte G. Nicoletti F. Libra M. Milella M. Tafuri A. Bonati A. Bäsecke J. Cocco L. Evangelisti C. Martelli A. M. Montalto G. Cervello M. McCubrey J. A. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 2011;3(3):192–222. doi: 10.18632/aging.100296. [DOI] [PMC free article] [PubMed] [Google Scholar]
Guo Y. J. Pan W. W. Liu S. B. Shen Z. F. Xu Y. Hu L. L. ERK/MAPK signalling pathway and tumorigenesis (Review) Exp. Ther. Med. 2020;19(3):1997–2007. doi: 10.3892/etm.2020.8454. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bousoik E. Montazeri Aliabadi H. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway. Front. Oncol. 2018;8:287. doi: 10.3389/fonc.2018.00287. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wu X. Yang H. Yu X. Qin J. J. Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies. Front. Pharmacol. 2022;13:1012552. doi: 10.3389/fphar.2022.1012552. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tang Q. Peng T. Hu J. Zhang T. Chen P. Chen D. Wang Y. Chen L. Tong L. Chen Y. Xie H. Liang G. Discovery of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine as an effective molecular skeleton to develop reversible/irreversible pan-HER inhibitors. Eur. J. Med. Chem. 2022;233:114249. doi: 10.1016/j.ejmech.2022.114249. [DOI] [PubMed] [Google Scholar]
Sever B. Otsuka M. Fujita M. Ciftci H. Design, Synthesis, and Anticancer Evaluation of New Small-Molecule EGFR Inhibitors Targeting NSCLC and Breast Cancer. Int. J. Mol. Sci. 2025;26(15):7065. doi: 10.3390/ijms26157065. [DOI] [PMC free article] [PubMed] [Google Scholar]
Serag M. I. Tawfik S. S. Badr S. M. I. Eisa H. M. New oxadiazole and pyrazoline derivatives as anti-proliferative agents targeting EGFR-TK: design, synthesis, biological evaluation and molecular docking study. Sci. Rep. 2024;14(1):5474. doi: 10.1038/s41598-024-55046-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
Sobh E. A. Khalil N. A. Faggal S. I. Hassan M. S. A. New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF-7 breast cancer cell line. Drug Dev. Res. 2022;83(5):1075–1096. doi: 10.1002/ddr.21934. [DOI] [PubMed] [Google Scholar]
Lin S. Zhang X. Yu Z. Huang X. Xu J. Liu Y. Wu L. Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers. Bioorg. Med. Chem. 2022;61:116739. doi: 10.1016/j.bmc.2022.116739. [DOI] [PubMed] [Google Scholar]
Bai X. Sun P. Wang X. Long C. Liao S. Dang S. Zhuang S. Du Y. Zhang X. Li N. He K. Zhang Z. Structure and dynamics of the EGFR/HER2 heterodimer. Cell Discovery. 2023;9(1):18. doi: 10.1038/s41421-023-00523-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Swain S. M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug Discovery. 2023;22(2):101–126. doi: 10.1038/s41573-022-00579-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ishikawa T. Seto M. Banno H. Kawakita Y. Oorui M. Taniguchi T. Ohta Y. Tamura T. Nakayama A. Miki H. Kamiguchi H. Tanaka T. Habuka N. Sogabe S. Yano J. Aertgeerts K. Kamiyama K. Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold. J. Med. Chem. 2011;54(23):8030–8050. doi: 10.1021/jm2008634. [DOI] [PubMed] [Google Scholar]
Fedele P. Sanna V. Santoro A. N. Iaia M. L. Fancellu A. Tailoring antiHer2 treatment strategies in breast cancer and beyond. Curr. Probl. Cancer. 2022;46(5):100892. doi: 10.1016/j.currproblcancer.2022.100892. [DOI] [PubMed] [Google Scholar]
Wilding B. Woelflingseder L. Baum A. Chylinski K. Vainorius G. Gibson N. Waizenegger I. C. Gerlach D. Augsten M. Spreitzer F. Shirai Y. Ikegami M. Tilandyová S. Scharn D. Pearson M. A. Popow J. Obenauf A. C. Yamamoto N. Kondo S. Opdam F. L. Bruining A. Kohsaka S. Kraut N. Heymach J. V. Solca F. Neumüller R. A. Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers. Cancer Discovery. 2025;15(1):119–138. doi: 10.1158/2159-8290.CD-24-0306. https://dx.doi.org/10.1158/2159-8290.Cd-24-0306 [DOI] [PMC free article] [PubMed] [Google Scholar]
Hurvitz S. Simonelli M. Yarza R. Berz D. Kitano S. Del Conte G. Acosta Eyzaguirre D. Doger de Speville Uribe B. G. Maier D. Erzen D. Aykut Yazgili S. Curigliano G. Deng T. Yan M. Zhang Q. Wang X. Nakayama I. Shitara K. Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers. Future Oncol. 2025;21(26):3385–3393. doi: 10.1080/14796694.2025.2569553. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang B. Yang Y. S. Yang N. Li G. Zhu H. L. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors. Sci. Rep. 2016;6:27571. doi: 10.1038/srep27571. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ibrahim N. S. M. Kadry H. H. Zaher A. F. Mohamed K. O. Synthesis of novel pyrimido[4,5-b]quinolines as potential anticancer agents and HER2 inhibitors. Chem. Biol. Drug Des. 2023;102(5):996–1013. doi: 10.1111/cbdd.14307. [DOI] [PubMed] [Google Scholar]
Mogheith S. M. Allam H. A. Ezzat M. A. F. Khan I. Fandy T. E. Dawud D. Abd Elmageed Z. Y. Albohy A. Ali H. I. Mohamady S. Design, novel one-pot green synthesis, and biological evaluation of pyrazolopyridine-congeners selectively targeting HER2+ breast cancer. Bioorg. Chem. 2025;163:108681. doi: 10.1016/j.bioorg.2025.108681. [DOI] [PubMed] [Google Scholar]
Arribas J. Baselga J. Pedersen K. Parra-Palau J. L. p95HER2 and breast cancer. Cancer Res. 2011;71(5):1515–1519. doi: 10.1158/0008-5472.CAN-10-3795. https://dx.doi.org/10.1158/0008-5472.can-10-3795 [DOI] [PubMed] [Google Scholar]
Mohan N. Jiang J. Dokmanovic M. Wu W. J. Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers. Antibody Ther. 2018;1(1):13–17. doi: 10.1093/abt/tby003. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schneeweiss A. Chia S. Hegg R. Tausch C. Deb R. Ratnayake J. McNally V. Ross G. Kiermaier A. Cortés J. Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014;16(4):R73. doi: 10.1186/bcr3690. [DOI] [PMC free article] [PubMed] [Google Scholar]
Musolino A. Ciccolallo L. Panebianco M. Fontana E. Zanoni D. Bozzetti C. Michiara M. Silini E. M. Ardizzoni A. Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study. Cancer. 2011;117(9):1837–1846. doi: 10.1002/cncr.25771. [DOI] [PubMed] [Google Scholar]
Elwaie T. A. Abbas S. E. Aly E. I. George R. F. Ali H. Kraiouchkine N. Abdelwahed K. S. Fandy T. E. El Sayed K. A. Abd Elmageed Z. Y. Ali H. I. HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and In Vitro and In Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability. J. Med. Chem. 2020;63(24):15906–15945. doi: 10.1021/acs.jmedchem.0c01647. [DOI] [PubMed] [Google Scholar]
Gavriil E. S. Doukatas A. Karampelas T. Myrianthopoulos V. Dimitrakis S. Mikros E. Marakos P. Tamvakopoulos C. Pouli N. Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy. Eur. J. Med. Chem. 2019;176:393–409. doi: 10.1016/j.ejmech.2019.05.029. [DOI] [PubMed] [Google Scholar]
Milik S. N. Abdel-Aziz A. K. Lasheen D. S. Serya R. A. T. Minucci S. Abouzid K. A. M. Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors. Eur. J. Med. Chem. 2018;155:316–336. doi: 10.1016/j.ejmech.2018.06.011. [DOI] [PubMed] [Google Scholar]
Li D. D. Qin Y. J. Sun J. Li J. R. Fang F. Du Q. R. Qian Y. Gong H. B. Zhu H. L. Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors. PLoS One. 2013;8(8):e69427. doi: 10.1371/journal.pone.0069427. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fakhry M. M. Mattar A. A. Alsulaimany M. Al-Olayan E. M. Al-Rashood S. T. Abdel-Aziz H. A. New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study. Molecules. 2023;28(21):7455. doi: 10.3390/molecules28217455. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gomaa H. A. M. Shaker M. E. Alzarea S. I. Alsahli T. G. Alanazi A. S. Mohamed F. A. M. Alanazi M. N. Abou-Zied H. A. Abdelmoez A. Brase S. Youssif B. G. M. Maghraby M. T. E. Design, synthesis, and apoptotic antiproliferative efficacy of new quinazoline/1,3,4-oxadiazole-2-thione derived EGFR/HER-2 dual inhibitors with anti-breast cancer activity. RSC Med. Chem. 2025;16(9):4297–4315. doi: 10.1039/D5MD00454C. [DOI] [PMC free article] [PubMed] [Google Scholar]
Salem I. M. El-Sabbagh O. I. Mostafa S. M. Salama I. Al-Awadh M. A. Alkhilaiwi F. A. Yonbawi A. R. Binothman N. Hayallah A. M. Ibrahim T. S. Exploitation of novel pyrazolo[3,4-d]pyrimidine scaffold tethered to thiazole as potential EGFR/HER2 dual kinase inhibitor to overcome lapatinib resistant breast cancer: Design, synthesis, in silico docking and molecular dynamic simulation. Bioorg. Chem. 2025;163:108671. doi: 10.1016/j.bioorg.2025.108671. [DOI] [PubMed] [Google Scholar]
Al-Wahaibi L. H. El-Sheref E. M. Tawfeek H. N. Abou-Zied H. A. Rabea S. M. Bräse S. Youssif B. G. M. Design, synthesis, and biological evaluation of novel quinoline-based EGFR/HER-2 dual-target inhibitors as potential anti-tumor agents. RSC Adv. 2024;14(45):32978–32991. doi: 10.1039/D4RA06394E. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hao S. Wang J.-h. Hou L. Liang J.-w. Yan J.-h. Niu Y.-f. Li X.-y. Sun Q. Meng F.-h. Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents. Bioorg. Chem. 2024;151:107686. doi: 10.1016/j.bioorg.2024.107686. [DOI] [PubMed] [Google Scholar]
Sabry M. A. Ghaly M. A. Maarouf A. R. El-Subbagh H. I. New thiazole-based derivatives as EGFR/HER2 and DHFR inhibitors: Synthesis, molecular modeling simulations and anticancer activity. Eur. J. Med. Chem. 2022;241:114661. doi: 10.1016/j.ejmech.2022.114661. [DOI] [PubMed] [Google Scholar]
Wu Z. Wang J. You F. Li X. Xiao C. The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer. Front. Pharmacol. 2023;14:1142087. doi: 10.3389/fphar.2023.1142087. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cross D. A. E. Ashton S. E. Ghiorghiu S. Eberlein C. Nebhan C. A. Spitzler P. J. Orme J. P. Finlay M. R. V. Ward R. A. Mellor M. J. Hughes G. Rahi A. Jacobs V. N. Brewer M. R. Ichihara E. Sun J. Jin H. Ballard P. Al-Kadhimi K. Rowlinson R. Klinowska T. Richmond G. H. P. Cantarini M. Kim D.-W. Ranson M. R. Pao W. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discovery. 2014;4(9):1046–1061. doi: 10.1158/2159-8290.CD-14-0337. https://dx.doi.org/10.1158/2159-8290.Cd-14-0337 [DOI] [PMC free article] [PubMed] [Google Scholar]
Liu H.-N. Zhu Y. Chi Y. Zhang Y. Li X. Wen W. Shan L.-S. Wang Y.-T. Dai B. Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy. Bioorg. Chem. 2024;151:107653. doi: 10.1016/j.bioorg.2024.107653. [DOI] [PubMed] [Google Scholar]
Das D. Xie L. Wang J. Xu X. Zhang Z. Shi J. Le X. Hong J. Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities - Part 1. Bioorg. Med. Chem. Lett. 2019;29(4):591–596. doi: 10.1016/j.bmcl.2018.12.056. [DOI] [PubMed] [Google Scholar]
Yin S. Tang C. Wang B. Zhang Y. Zhou L. Xue L. Zhang C. Design, synthesis and biological evaluation of novel EGFR/HER2 dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1H)-one scaffold. Eur. J. Med. Chem. 2016;120:26–36. doi: 10.1016/j.ejmech.2016.04.072. [DOI] [PubMed] [Google Scholar]
Lin S. Li Y. Zheng Y. Luo L. Sun Q. Ge Z. Cheng T. Li R. Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs. Eur. J. Med. Chem. 2017;127:442–458. doi: 10.1016/j.ejmech.2016.12.055. [DOI] [PubMed] [Google Scholar]
Mahboobi S. Sellmer A. Winkler M. Eichhorn E. Pongratz H. Ciossek T. Baer T. Maier T. Beckers T. Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity. J. Med. Chem. 2010;53(24):8546–8555. doi: 10.1021/jm100665z. [DOI] [PubMed] [Google Scholar]
Chen C. H. Chen M. C. Wang J. C. Tsai A. C. Chen C. S. Liou J. P. Pan S. L. Teng C. M. Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo. Clin. Cancer Res. 2014;20(5):1274–1287. doi: 10.1158/1078-0432.CCR-12-3909. https://dx.doi.org/10.1158/1078-0432.Ccr-12-3909 [DOI] [PMC free article] [PubMed] [Google Scholar]
Greve G. Schiffmann I. Pfeifer D. Pantic M. Schüler J. Lübbert M. The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells. BMC Cancer. 2015;15:947. doi: 10.1186/s12885-015-1967-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tanimoto A. Takeuchi S. Arai S. Fukuda K. Yamada T. Roca X. Ong S. T. Yano S. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. Clin. Cancer Res. 2017;23(12):3139–3149. doi: 10.1158/1078-0432.CCR-16-2271. https://dx.doi.org/10.1158/1078-0432.Ccr-16-2271 [DOI] [PubMed] [Google Scholar]
Graves L. M. Duncan J. S. Whittle M. C. Johnson G. L. The dynamic nature of the kinome. Biochem. J. 2013;450(1):1–8. doi: 10.1042/BJ20121456. https://dx.doi.org/10.1042/bj20121456 [DOI] [PMC free article] [PubMed] [Google Scholar]
Qi S.-M. Dong J. Xu Z.-Y. Cheng X.-D. Zhang W.-D. Qin J.-J. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front. Pharmacol. 2021;12:692574. doi: 10.3389/fphar.2021.692574. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bricelj A. Steinebach C. Kuchta R. Gütschow M. Sosič I. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Front. Chem. 2021;9:707317. doi: 10.3389/fchem.2021.707317. [DOI] [PMC free article] [PubMed] [Google Scholar]
Burslem G. M. Smith B. E. Lai A. C. Jaime-Figueroa S. McQuaid D. C. Bondeson D. P. Toure M. Dong H. Qian Y. Wang J. Crew A. P. Hines J. Crews C. M. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem. Biol. 2018;25(1):67–77. doi: 10.1016/j.chembiol.2017.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chaudhari P. J. Nemade A. R. Shirkhedkar A. A. Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents. RSC Adv. 2024;14(45):33384–33417. doi: 10.1039/D4RA05244G. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yan J. D. Liu Y. Zhang Z. Y. Liu G. Y. Xu J. H. Liu L. Y. Hu Y. M. Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol., Res. Pract. 2015;211(7):539–543. doi: 10.1016/j.prp.2015.04.003. [DOI] [PubMed] [Google Scholar]
Hanna P. E. Anumolu R. K. Motwani S. S. Chen K. L. Katz-Agranov N. Green-Lingren O. Yilmam O. A. Jhaveri K. D. Kitchlu A. Kala J. Sise M. E. Gupta S. Risk Factors for Severe Hypertension and Proteinuria After Treatment With Vascular Endothelial Growth Factor Signaling Pathway Inhibitors Among Patients With Cancer. Kidney Int. Rep. 2024;9(6):1897–1902. doi: 10.1016/j.ekir.2024.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
Uyl T. J. J. Ngo A. Pratt D. Cortez I. Mathijssen R. H. J. Versmissen J. Danser A. H. J. Mirabito Colafella K. M. Mechanisms of anti-VEGF therapy-induced kidney injury: current insights and future perspectives in combination with immune checkpoint inhibitors. Am. J. Physiol. 2025;329(2):F284–F299. doi: 10.1152/ajprenal.00081.2025. [DOI] [PubMed] [Google Scholar]
Lee J. H. Shim J. W. Choi Y. J. Heo K. Yang K. The combination of sorafenib and radiation preferentially inhibits breast cancer stem cells by suppressing HIF-1α expression. Oncol. Rep. 2013;29(3):917–924. doi: 10.3892/or.2013.2228. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li X. Wu C. Lin X. Cai X. Liu L. Luo G. You Q. Xiang H. Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2. Eur. J. Med. Chem. 2019;161:445–455. doi: 10.1016/j.ejmech.2018.10.045. [DOI] [PubMed] [Google Scholar]
Luo G. Li X. Zhang G. Wu C. Tang Z. Liu L. You Q. Xiang H. Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer. Eur. J. Med. Chem. 2017;140:252–273. doi: 10.1016/j.ejmech.2017.09.015. [DOI] [PubMed] [Google Scholar]
Elgammal W. E. Elkady H. Mahdy H. A. Elwan A. Husein D. Z. Amin F. G. Alsfouk B. A. Elkaeed E. B. Eissa I. H. Metwaly A. M. 2,3-Dihydro-1,3,4-thiadiazoles as dual B-Raf/VEGFR-2 inhibitors: Design, synthesis, and anti-breast cancer assessment. J. Mol. Struct. 2026;1354:144717. doi: 10.1016/j.molstruc.2025.144717. [DOI] [Google Scholar]
Abdelgawad M. A. Hayallah A. M. Bukhari S. N. A. Musa A. Elmowafy M. Abdel-Rahman H. M. Abd El-Gaber M. K. Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold. Pharmaceuticals. 2022;15(11):1416. doi: 10.3390/ph15111416. [DOI] [PMC free article] [PubMed] [Google Scholar]
Eissa I. H. Elwan A. Al-Qadhi M. A. Husein D. Z. Amin F. G. Alsfouk A. A. Elkaeed E. B. Elkady H. Metwaly A. M. Targeting VEGFR-2 in breast cancer: synthesis and in silico and in vitro characterization of quinoxaline-based inhibitors. RSC Adv. 2025;15(17):12896–12916. doi: 10.1039/D5RA00526D. [DOI] [PMC free article] [PubMed] [Google Scholar]
El Hamaky N. F. M. Hamdi A. Bayoumi W. A. Elgazar A. A. Nasr M. N. A. Design, synthesis, and biological evaluation of quinazoline–benzohydrazide and quinazoline–benzothiazole hybrids uncovering a dual EGFR/VEGFR-2 inhibitor with pronounced cytotoxic activity against triple-negative breast Cancer. Bioorg. Med. Chem. 2026;133:118515. doi: 10.1016/j.bmc.2025.118515. [DOI] [PubMed] [Google Scholar]
Yousef R. G. El-Metwally S. A. Ward M. M. S. A. Alsfouk A. A. Husein D. Z. Soliman O. A. Elkaeed E. B. Elkady H. Metwaly A. M. Eissa I. H. Discovery of new thieno[2,3-d]pyrimidine-based dual VEGFR-2 and EGFR inhibitors for enhanced therapeutic efficacy in breast cancer. J. Mol. Struct. 2025;1341:142586. doi: 10.1016/j.molstruc.2025.142586. [DOI] [Google Scholar]
Mahmoud M. A. Mohammed A. F. Salem O. I. A. Almutairi T. M. Bräse S. Youssif B. G. M. Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors. J. Enzyme Inhib. Med. Chem. 2024;39(1):2305856. doi: 10.1080/14756366.2024.2305856. [DOI] [PMC free article] [PubMed] [Google Scholar]
Al-Wahaibi L. H. Elshamsy A. M. Ali T. F. S. Youssif B. G. M. Bräse S. Abdel-Aziz M. El-Koussi N. A. Design and Synthesis of New Dihydropyrimidine Derivatives with a Cytotoxic Effect as Dual EGFR/VEGFR-2 Inhibitors. ACS Omega. 2024;9(32):34358–34369. doi: 10.1021/acsomega.4c01361. [DOI] [PMC free article] [PubMed] [Google Scholar]
Peng F. W. Xuan J. Wu T. T. Xue J. Y. Ren Z. W. Liu D. K. Wang X. Q. Chen X. H. Zhang J. W. Xu Y. G. Shi L. Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC. Eur. J. Med. Chem. 2016;109:1–12. doi: 10.1016/j.ejmech.2015.12.033. [DOI] [PubMed] [Google Scholar]
Jansson S. Aaltonen K. Bendahl P. O. Falck A. K. Karlsson M. Pietras K. Rydén L. The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res. Treat. 2018;169(2):231–241. doi: 10.1007/s10549-018-4664-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen P. H. Chen X. He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim. Biophys. Acta. 2013;1834(10):2176–2186. doi: 10.1016/j.bbapap.2012.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang L. Li N. Xue Z. Liu L.-R. Li J. Huang X. Xie X. Zou Y. Tang H. Xie X. Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer. Cell Death Differ. 2020;27(7):2066–2080. doi: 10.1038/s41418-019-0485-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Joglekar-Javadekar M. Van Laere S. Bourne M. Moalwi M. Finetti P. Vermeulen P. B. Birnbaum D. Dirix L. Y. Ueno N. Carter M. Rains J. Ramachandran A. Bertucci F. van Golen K. L. Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC) Neoplasia. 2017;19(7):564–573. doi: 10.1016/j.neo.2017.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tan L., Wang J. and Xu W., Crystal Structure of PDGFRA T674I in Complex with Crenolanib. Protein Data Bank, 2019, PDB: 6JOI, 10.2210/pdb6joi/pdb [DOI] [Google Scholar]
Yao D. Zhou Y. Zhu L. Ouyang L. Zhang J. Jiang Y. Zhao Y. Sun D. Yang S. Yu Y. Wang J. Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer. Eur. J. Med. Chem. 2017;140:155–171. doi: 10.1016/j.ejmech.2017.08.067. [DOI] [PubMed] [Google Scholar]
Iweala E. E. J. Amuji D. N. Oluwajembola A. M. Ugbogu E. A. Targeting c-Met in breast cancer: From mechanisms of chemoresistance to novel therapeutic strategies. Curr. Res. Pharmacol. Drug Discovery. 2024;7:100204. doi: 10.1016/j.crphar.2024.100204. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jeon H.-M. Lee J. MET: roles in epithelial-mesenchymal transition and cancer stemness. Ann. Transl. Med. 2017;5(1):5. doi: 10.21037/atm.2016.12.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ji X. Meng X. He Q. Xiang X. Shi Y. Zhu X. Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling. Int. J. Mol. Sci. 2023;24(1):757. doi: 10.3390/ijms24010757. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang Z. Shi Z. Yang S. Niu Z. Shu K. Chen L. Zhi C. Liu F. Huang W. Fan T. Jiang Y. Design and Synthesis of c-Met and HDAC Dual Inhibitors for the Treatment of Breast Cancer. ACS Med. Chem. Lett. 2024;15(9):1516–1525. doi: 10.1021/acsmedchemlett.4c00256. [DOI] [PMC free article] [PubMed] [Google Scholar]
Sun Z. Li L. Zhai B. Hu M. Huang L. Huang S. Ye L. Kong X. Xu J. Bai J. Yan J. Zhou Q. Hu Z. Zhang Y. Jiang Y. Zhang Y. Qiao Z. Zou Y. Xu Y. Zhu Q. Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression. J. Med. Chem. 2024;67(6):4916–4935. doi: 10.1021/acs.jmedchem.4c00077. [DOI] [PubMed] [Google Scholar]
Naguib B. H. Elsebaie H. A. Nafie M. S. Mohamady S. Albujuq N. R. Samir Ayed A. Nada D. Khalil A. F. Hefny S. M. Tawfik H. O. Shaldam M. A. Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents. Bioorg. Chem. 2024;151:107682. doi: 10.1016/j.bioorg.2024.107682. [DOI] [PubMed] [Google Scholar]
Francavilla C. O’Brien C. S. Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer. Open Biol. 2022;12(2):210373. doi: 10.1098/rsob.210373. [DOI] [PMC free article] [PubMed] [Google Scholar]
Sohl C. D. Ryan M. R. Luo B. Frey K. M. Anderson K. S. Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles’ Heel of Targeted Therapy. ACS Chem. Biol. 2015;10(5):1319–1329. doi: 10.1021/acschembio.5b00014. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kalyukina M. Yosaatmadja Y. Middleditch M. J. Patterson A. V. Smaill J. B. Squire C. J. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem. 2019;14(4):494–500. doi: 10.1002/cmdc.201800719. [DOI] [PubMed] [Google Scholar]
Guffanti F. Chilà R. Bello E. Zucchetti M. Zangarini M. Ceriani L. Ferrari M. Lupi M. Jacquet-Bescond A. Burbridge M. F. Pierrat M. J. Damia G. In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models. Neoplasia. 2017;19(1):35–42. doi: 10.1016/j.neo.2016.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hui R. Pearson A. Cortes J. Campbell C. Poirot C. Azim Jr. H. A. Fumagalli D. Lambertini M. Daly F. Arahmani A. Perez-Garcia J. Aftimos P. Bedard P. L. Xuereb L. Scheepers E. D. Vicente M. Goulioti T. Loibl S. Loi S. Pierrat M. J. Turner N. C. Andre F. Curigliano G. Lucitanib for the Treatment of HR(+)/HER2(-) Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study. Clin. Cancer Res. 2020;26(2):354–363. doi: 10.1158/1078-0432.CCR-19-1164. https://dx.doi.org/10.1158/1078-0432.Ccr-19-1164 [DOI] [PubMed] [Google Scholar]
Meric-Bernstam F. Bahleda R. Hierro C. Sanson M. Bridgewater J. Arkenau H. T. Tran B. Kelley R. K. Park J. O. Javle M. He Y. Benhadji K. A. Goyal L. Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study. Cancer Discovery. 2022;12(2):402–415. doi: 10.1158/2159-8290.CD-21-0697. https://dx.doi.org/10.1158/2159-8290.Cd-21-0697 [DOI] [PMC free article] [PubMed] [Google Scholar]
Sootome H. Fujita H. Ito K. Ochiiwa H. Fujioka Y. Ito K. Miura A. Sagara T. Ito S. Ohsawa H. Otsuki S. Funabashi K. Yashiro M. Matsuo K. Yonekura K. Hirai H. Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020;80(22):4986–4997. doi: 10.1158/0008-5472.CAN-19-2568. https://dx.doi.org/10.1158/0008-5472.Can-19-2568 [DOI] [PubMed] [Google Scholar]
Chen Z. Tong L.-j. Tang B.-y. Liu H.-y. Wang X. Zhang T. Cao X.-w. Chen Y. Li H.-l. Qian X.-h. Xu Y.-f. Xie H. Ding J. C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis. Acta Pharmacol. Sin. 2019;40(6):823–832. doi: 10.1038/s41401-018-0191-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ashraf-Uz-Zaman M. Shahi S. Akwii R. Sajib M. S. Farshbaf M. J. Kallem R. R. Putnam W. Wang W. Zhang R. Alvina K. Trippier P. C. Mikelis C. M. German N. A. Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer. Eur. J. Med. Chem. 2021;209:112866. doi: 10.1016/j.ejmech.2020.112866. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lang L. Teng Y. Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies. Cells. 2019;8(1) doi: 10.3390/cells8010031. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mo C. Zhang Z. Guise C. P. Li X. Luo J. Tu Z. Xu Y. Patterson A. V. Smaill J. B. Ren X. Lu X. Ding K. 2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors. ACS Med. Chem. Lett. 2017;8(5):543–548. doi: 10.1021/acsmedchemlett.7b00091. [DOI] [PMC free article] [PubMed] [Google Scholar]
Krämer J. Bar-Or A. Turner T. J. Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat. Rev. Neurol. 2023;19(5):289–304. doi: 10.1038/s41582-023-00800-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Burger J. A. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr. Hematol. Malig. Rep. 2014;9(1):44–49. doi: 10.1007/s11899-013-0188-8. [DOI] [PubMed] [Google Scholar]
Wang X. Kokabee L. Kokabee M. Conklin D. S. Bruton's Tyrosine Kinase and Its Isoforms in Cancer. Front. Cell Dev. Biol. 2021;9:668996. doi: 10.3389/fcell.2021.668996. [DOI] [PMC free article] [PubMed] [Google Scholar]
Varikuti S. Singh B. Volpedo G. Ahirwar D. K. Jha B. K. Saljoughian N. Viana A. G. Verma C. Hamza O. Halsey G. Holcomb E. A. Maryala R. J. Oghumu S. Ganju R. K. Satoskar A. R. Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells. Br. J. Cancer. 2020;122(7):1005–1013. doi: 10.1038/s41416-020-0743-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen J. Kinoshita T. Sukbuntherng J. Chang B. Y. Elias L. Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth. Mol. Cancer Ther. 2016;15(12):2835–2844. doi: 10.1158/1535-7163.MCT-15-0923. https://dx.doi.org/10.1158/1535-7163.Mct-15-0923 [DOI] [PubMed] [Google Scholar]
Dostálová H. Jorda R. Řezníčková E. Kryštof V. Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines. Invest. New Drugs. 2023;41(2):210–219. doi: 10.1007/s10637-023-01346-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bender A. T. Gardberg A. Pereira A. Johnson T. Wu Y. Grenningloh R. Head J. Morandi F. Haselmayer P. Liu-Bujalski L. Ability of Bruton’s Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling. Mol. Pharmacol. 2017;91(3):208–219. doi: 10.1124/mol.116.107037. [DOI] [PubMed] [Google Scholar]
Guo Y. Liu Y. Hu N. Yu D. Zhou C. Shi G. Zhang B. Wei M. Liu J. Luo L. Tang Z. Song H. Guo Y. Liu X. Su D. Zhang S. Song X. Zhou X. Hong Y. Chen S. Cheng Z. Young S. Wei Q. Wang H. Wang Q. Lv L. Wang F. Xu H. Sun H. Xing H. Li N. Zhang W. Wang Z. Liu G. Sun Z. Zhou D. Li W. Liu L. Wang L. Wang Z. Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. J. Med. Chem. 2019;62(17):7923–7940. doi: 10.1021/acs.jmedchem.9b00687. [DOI] [PubMed] [Google Scholar]
Sulzmaier F. J. Jean C. Schlaepfer D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer. 2014;14(9):598–610. doi: 10.1038/nrc3792. [DOI] [PMC free article] [PubMed] [Google Scholar]
Murphy J. M. Rodriguez Y. A. R. Jeong K. Ahn E.-Y. E. Lim S.-T. S. Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp. Mol. Med. 2020;52(6):877–886. doi: 10.1038/s12276-020-0447-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Paul R. Luo M. Mo X. Lu J. Yeo S. K. Guan J.-L. FAK activates AKT-mTOR signaling to promote the growth and progression of MMTV-Wnt1-driven basal-like mammary tumors. Breast Cancer Res. 2020;22(1):59. doi: 10.1186/s13058-020-01298-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fukami S. Tomioka D. Murakami Y. Honda T. Hatakeyama S. Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo tumor models. BMC Res. Notes. 2019;12(1):347. doi: 10.1186/s13104-019-4389-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang L. Ai M. Yu J. Jin L. Wang C. Liu Z. Shu X. Tang Z. Liu K. Luo H. Guan W. Sun X. Ma X. Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells. Eur. J. Med. Chem. 2019;172:154–162. doi: 10.1016/j.ejmech.2019.04.004. [DOI] [PubMed] [Google Scholar]
Groendyke B. J. Nabet B. Mohardt M. L. Zhang H. Peng K. Koide E. Coffey C. R. Che J. Scott D. A. Bass A. J. Gray N. S. Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor. ACS Med. Chem. Lett. 2021;12(1):30–38. doi: 10.1021/acsmedchemlett.0c00338. [DOI] [PMC free article] [PubMed] [Google Scholar]
Portugal C. C. Almeida T. O. Socodato R. Relvas J. B. Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases. FEBS J. 2022;289(24):7760–7775. doi: 10.1111/febs.16197. [DOI] [PubMed] [Google Scholar]
Alper O. Bowden E. T. Novel Insights Into c-Src. Curr. Pharm. Des. 2005;11(9):1119–1130. doi: 10.2174/1381612053507576. [DOI] [PubMed] [Google Scholar]
Parks E. E. Ceresa B. P. Cell surface epidermal growth factor receptors increase Src and c-Cbl activity and receptor ubiquitylation. J. Biol. Chem. 2014;289(37):25537–25545. doi: 10.1074/jbc.M114.579581. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen Z. Oh D. Dubey A. K. Yao M. Yang B. Groves J. T. Sheetz M. EGFR family and Src family kinase interactions: mechanics matters? Curr. Opin. Cell Biol. 2018;51:97–102. doi: 10.1016/j.ceb.2017.12.003. [DOI] [PubMed] [Google Scholar]
Campbell E. J. McDuff E. Tatarov O. Tovey S. Brunton V. Cooke T. G. Edwards J. Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer. Br. J. Cancer. 2008;99(11):1769–1774. doi: 10.1038/sj.bjc.6604768. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zhang S. Huang W. C. Li P. Guo H. Poh S. B. Brady S. W. Xiong Y. Tseng L. M. Li S. H. Ding Z. Sahin A. A. Esteva F. J. Hortobagyi G. N. Yu D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 2011;17(4):461–469. doi: 10.1038/nm.2309. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fraser C. Dawson J. C. Dowling R. Houston D. R. Weiss J. T. Munro A. F. Muir M. Harrington L. Webster S. P. Frame M. C. Brunton V. G. Patton E. E. Carragher N. O. Unciti-Broceta A. Rapid Discovery and Structure–Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. J. Med. Chem. 2016;59(10):4697–4710. doi: 10.1021/acs.jmedchem.6b00065. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zou L. Yadav U. P. Marianesan A. B. Kumar R. Singh T. G. Verma A. Alasiri G. Fareed M. Alam P. Sathish E. Huang Y. Design and synthesis of tetrazole tethered quinazoline derivatives via azide-isocyanide cross-coupling reaction: Exploring the utility as anticancer agents via the SRC kinase inhibition in breast cancer. Bioorg. Chem. 2025;164:108844. doi: 10.1016/j.bioorg.2025.108844. [DOI] [PubMed] [Google Scholar]
Wang Y. Huang A. Chen L. Sun F. Zhao M. Zhang M. Xie Y. Xu S. Li M. Hong L. Li G. Wang R. Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer. Eur. J. Med. Chem. 2024;264:116009. doi: 10.1016/j.ejmech.2023.116009. [DOI] [PubMed] [Google Scholar]
Brandvold K. R. Steffey M. E. Fox C. C. Soellner M. B. Development of a Highly Selective c-Src Kinase Inhibitor. ACS Chem. Biol. 2012;7(8):1393–1398. doi: 10.1021/cb300172e. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ko K. S. Steffey M. E. Brandvold K. R. Soellner M. B. Development of a chimeric c-Src kinase and HDAC inhibitor. ACS Med. Chem. Lett. 2013;4(8):779–783. doi: 10.1021/ml400175d. [DOI] [PMC free article] [PubMed] [Google Scholar]
Agashe R. P. Lippman S. M. Kurzrock R. JAK: Not Just Another Kinase. Mol. Cancer Ther. 2022;21(12):1757–1764. doi: 10.1158/1535-7163.MCT-22-0323. https://dx.doi.org/10.1158/1535-7163.Mct-22-0323 [DOI] [PMC free article] [PubMed] [Google Scholar]
Jin W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition. Cells. 2020;9(1):217. doi: 10.3390/cells9010217. [DOI] [PMC free article] [PubMed] [Google Scholar]
Moon S. Y. Lee H. Kim S. Hong J. H. Chun S. H. Lee H. Y. Kang K. Kim H. S. Won H. S. Ko Y. H. Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells. BMC Cancer. 2021;21(1):931. doi: 10.1186/s12885-021-08641-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kim J. W. Gautam J. Kim J. E. Kim J. A. Kang K. W. Inhibition of tumor growth and angiogenesis of tamoxifen-resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor. Oncol. Lett. 2019;17(4):3981–3989. doi: 10.3892/ol.2019.10059. [DOI] [PMC free article] [PubMed] [Google Scholar]
You K. S. Kim T.-S. Back S. M. Park J.-S. Liu K. Seong Y.-S. Kim D. J. Yi Y. W. JAK2 Inhibition Augments the Anti-Proliferation Effects by AKT and MEK Inhibition in Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2025;26(13):6139. doi: 10.3390/ijms26136139. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang E. G. Mustafa N. Tan E. C. Poulsen A. Ramanujulu P. M. Chng W. J. Yen J. J. Dymock B. W. Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines. J. Med. Chem. 2016;59(18):8233–8262. doi: 10.1021/acs.jmedchem.6b00157. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No new data were generated or analyzed in support of this review article. Therefore, no research data is associated with this manuscript.

[cit1] Bray F. Laversanne M. Sung H. Ferlay J. Siegel R. L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J. Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]

[cit2] Wilkinson L. Gathani T. Understanding breast cancer as a global health concern. Br. J. Radiol. 2022;95(1130):20211033. doi: 10.1259/bjr.20211033. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit3] National Cancer Institute website, Cancer Stat Facts: Female Breast Cancer, 2024, Available from: https://seer.cancer.gov/statfacts/html/breast.html

[cit4] Tufail M. Cui J. Wu C. Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches. Am. J. Cancer Res. 2022;12(7):2920–2949. [PMC free article] [PubMed] [Google Scholar]

[cit5] Orrantia-Borunda E., Anchondo-Nuñez P., Acuña-Aguilar L. E., Gómez-Valles F. O. and Ramírez-Valdespino C. A., Subtypes of Breast Cancer, in Breast Cancer, H. N. Mayrovitz, Exon Publications, Brisbane (AU), Copyright: The Authors.; The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced., 2022 [Google Scholar]

[cit6] Orrantia-Borunda E., Anchondo-Nuñez P., Acuña-Aguilar L. E., Gómez-Valles F. O. and Ramírez-Valdespino C. A., Subtypes of Breast Cancer. Cancer B, ed. H. N. Mayrovitz, Exon Publications, Brisbane, 2022 [PubMed] [Google Scholar]

[cit7] Eroles P. Bosch A. Alejandro Pérez-Fidalgo J. Lluch A. Molecular biology in breast cancer: Intrinsic subtypes and signaling pathways. Cancer Treat. Rev. 2012;38(6):698–707. doi: 10.1016/j.ctrv.2011.11.005. [DOI] [PubMed] [Google Scholar]

[cit8] Hsu J. L. Hung M. C. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016;35(4):575–588. doi: 10.1007/s10555-016-9649-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit9] Miziak P. Baran M. Błaszczak E. Przybyszewska-Podstawka A. Kałafut J. Smok-Kalwat J. Dmoszyńska-Graniczka M. Kiełbus M. Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers. 2023;15(19):4689. doi: 10.3390/cancers15194689. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit10] Rios-Hoyo A. Xiong K. Dai J. Yau C. Marczyk M. Garcia-Milian R. Wolf D. M. Huppert L. A. Nanda R. Hirst G. L. Cobain E. F. van ’t Veer L. J. Esserman L. J. Pusztai L. Hormone Receptor–Positive HER2-Negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple-Negative Breast Cancers. Clin. Cancer Res. 2025;31(2):403–413. doi: 10.1158/1078-0432.CCR-24-1553. https://dx.doi.org/10.1158/1078-0432.Ccr-24-1553 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit11] Mu Y. Meng Y. Du Y. Liu X. Zhang J. Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer. Thorac. Cancer. 2023;14(34):3381–3388. doi: 10.1111/1759-7714.15130. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit12] García-García C. Ibrahim Y. H. Serra V. Calvo M. T. Guzmán M. Grueso J. Aura C. Pérez J. Jessen K. Liu Y. Rommel C. Tabernero J. Baselga J. Scaltriti M. Dual mTORC1/2 and HER2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-HER2 Therapy. Clin. Cancer Res. 2012;18(9):2603–2612. doi: 10.1158/1078-0432.CCR-11-2750. https://dx.doi.org/10.1158/1078-0432.Ccr-11-2750 [DOI] [PubMed] [Google Scholar]

[cit13] Swain S. M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug Discovery. 2023;22(2):101–126. doi: 10.1038/s41573-022-00579-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit14] Oh D. Y. Bang Y. J. HER2-targeted therapies - a role beyond breast cancer. Nat. Rev. Clin. Oncol. 2020;17(1):33–48. doi: 10.1038/s41571-019-0268-3. [DOI] [PubMed] [Google Scholar]

[cit15] Escrivá-de-Romaní S. Arumí M. Bellet M. Saura C. HER2-positive breast cancer: Current and new therapeutic strategies. Breast. 2018;39:80–88. doi: 10.1016/j.breast.2018.03.006. [DOI] [PubMed] [Google Scholar]

[cit16] Nunnery S. E. Mayer I. A. Balko J. M. Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis. Cancer J. 2021;27(1):2–7. doi: 10.1097/PPO.0000000000000494. https://dx.doi.org/10.1097/ppo.0000000000000494 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit17] Lehmann B. D. Bauer J. A. Chen X. Sanders M. E. Chakravarthy A. B. Shyr Y. Pietenpol J. A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 2011;121(7):2750–2767. doi: 10.1172/JCI45014. https://dx.doi.org/10.1172/jci45014 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit18] Zangardi M. L. Spring L. M. Nagayama A. Bardia A. Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy? Expert Opin. Invest. Drugs. 2019;28(2):107–112. doi: 10.1080/13543784.2019.1555239. [DOI] [PubMed] [Google Scholar]

[cit19] Yeeravalli R. Das A. Molecular mediators of breast cancer metastasis. Hematology/Oncology and Stem. Cell Ther. 2021;14(4):275–289. doi: 10.1016/j.hemonc.2021.02.002. [DOI] [PubMed] [Google Scholar]

[cit20] Burcu B. Ertas I. Sener A. Demircioglu Z. G. Cerekci E. Kaya C. Retrospective Analysis of Parameters Affecting Metastatic Breast Cancer. Sisli Etfal Hastan Tip Bull. 2023;57(4):479–484. doi: 10.14744/SEMB.2023.94803. https://dx.doi.org/10.14744/semb.2023.94803 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit21] Guo L. Kong D. Liu J. Zhan L. Luo L. Zheng W. Zheng Q. Chen C. Sun S. Breast cancer heterogeneity and its implication in personalized precision therapy. Exp. Hematol. Oncol. 2023;12(1):3. doi: 10.1186/s40164-022-00363-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit22] Liu T. Song S. Wang X. Hao J. Small-molecule inhibitors of breast cancer-related targets: Potential therapeutic agents for breast cancer. Eur. J. Med. Chem. 2021;210:112954. doi: 10.1016/j.ejmech.2020.112954. [DOI] [PubMed] [Google Scholar]

[cit23] Ajayi E. D. Elazazy M. Abouzid K. Ali H. I. Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration. Eur. J. Med. Chem. 2026;301:118219. doi: 10.1016/j.ejmech.2025.118219. [DOI] [PubMed] [Google Scholar]

[cit24] Mo F. Pellerino A. Soffietti R. Rudà R. Blood-Brain Barrier in Brain Tumors: Biology and Clinical Relevance. Int. J. Mol. Sci. 2021;22(23):12654. doi: 10.3390/ijms222312654. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit25] Lockman P. R. Mittapalli R. K. Taskar K. S. Rudraraju V. Gril B. Bohn K. A. Adkins C. E. Roberts A. Thorsheim H. R. Gaasch J. A. Huang S. Palmieri D. Steeg P. S. Smith Q. R. Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer. Clin. Cancer Res. 2010;16(23):5664–5678. doi: 10.1158/1078-0432.CCR-10-1564. https://dx.doi.org/10.1158/1078-0432.Ccr-10-1564 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit26] Riecke K. Müller V. Neunhöffer T. Park-Simon T. W. Weide R. Polasik A. Schmidt M. Puppe J. Mundhenke C. Lübbe K. Hesse T. Thill M. Wuerstlein R. Denkert C. Decker T. Fehm T. Nekljudova V. Rey J. Loibl S. Laakmann E. Witzel I. Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry. ESMO Open. 2023;8(3):101213. doi: 10.1016/j.esmoop.2023.101213. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit27] Zimmer A. S. Van Swearingen A. E. D. Anders C. K. HER2-positive breast cancer brain metastasis: A new and exciting landscape. Cancer Rep. 2022;5(4):e1274. doi: 10.1002/cnr2.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit28] Yu Y. Huang K. Lin Y. Zhang J. Song C. Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis. Cancer Med. 2023;12(14):15090–15100. doi: 10.1002/cam4.6180. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit29] Guglielmi G. Zamagni C. Del Re M. Danesi R. Fogli S. Targeting HER2 in breast cancer with brain metastases: A pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments. Eur. J. Pharmacol. 2024;985:177076. doi: 10.1016/j.ejphar.2024.177076. [DOI] [PubMed] [Google Scholar]

[cit30] Cornelissen F. M. G. Markert G. Deutsch G. Antonara M. Faaij N. Bartelink I. Noske D. Vandertop W. P. Bender A. Westerman B. A. Explaining Blood–Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms. J. Med. Chem. 2023;66(11):7253–7267. doi: 10.1021/acs.jmedchem.2c01824. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit31] Yang H. Zhao Y. Wang Y. Ma X. Ling J. Zeng X. Li Z. Liao G. Triple-Negative Breast Cancer Brain Metastasis: A Comprehensive Review of Epidemiology, Molecular Pathobiology, and Therapeutic Frontiers. Cancers. 2026;18(7):1179. doi: 10.3390/cancers18071179. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit32] Liu Z. Li M. Zhao Z. Liu A. Sun P. Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases. Front. Oncol. 2024;14:1439984. doi: 10.3389/fonc.2024.1439984. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit33] Brognard J. Hunter T. Protein kinase signaling networks in cancer. Curr. Opin. Genet. Dev. 2011;21(1):4–11. doi: 10.1016/j.gde.2010.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit34] Du Z. Lovly C. M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer. 2018;17(1):58. doi: 10.1186/s12943-018-0782-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit35] Cheng H. C. Qi R. Z. Paudel H. Zhu H. J. Regulation and function of protein kinases and phosphatases. Enzym. Res. 2011;2011:794089. doi: 10.4061/2011/794089. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit36] Singh S. S. and Jois S. D., Chapter One - Homo- and Heterodimerization of Proteins in Cell Signaling: Inhibition and Drug Design, in Advances in Protein Chemistry and Structural Biology, ed. R. Donev, Academic Press, 2018, pp. 1–59 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit37] Lemmon M. A. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–1134. doi: 10.1016/j.cell.2010.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit38] Haubrich J. Zwier J. M. Charrier-Savournin F. Prézeau L. Pin J. P. Different EGF-induced receptor dimer conformations for signaling and internalization. FASEB J. 2024;38(1):e23356. doi: 10.1096/fj.202301209R. [DOI] [PubMed] [Google Scholar]

[cit39] Zhang Y. Alexander P. B. Wang X. F. TGF-β Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harbor Perspect. Biol. 2017;9(4):a022145. doi: 10.1101/cshperspect.a022145. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit40] Bansal I. Pandey A. K. Ruwali M. Small-molecule inhibitors of kinases in breast cancer therapy: recent advances, opportunities, and challenges. Front. Pharmacol. 2023;14:1244597. doi: 10.3389/fphar.2023.1244597. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit41] Gross S. Rahal R. Stransky N. Lengauer C. Hoeflich K. P. Targeting cancer with kinase inhibitors. J. Clin. Invest. 2015;125(5):1780–1789. doi: 10.1172/JCI76094. https://dx.doi.org/10.1172/jci76094 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit42] Bhullar K. S. Lagarón N. O. McGowan E. M. Parmar I. Jha A. Hubbard B. P. Rupasinghe H. P. V. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer. 2018;17(1):48. doi: 10.1186/s12943-018-0804-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit43] Arter C. Trask L. Ward S. Yeoh S. Bayliss R. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. J. Biol. Chem. 2022;298(8):102247. doi: 10.1016/j.jbc.2022.102247. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit44] Lee P. Y. Yeoh Y. Low T. Y. A recent update on small-molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry-based proteomic analysis. FASEB J. 2023;290(11):2845–2864. doi: 10.1111/febs.16442. [DOI] [PubMed] [Google Scholar]

[cit45] Vijayan R. S. K. He P. Modi V. Duong-Ly K. C. Ma H. Peterson J. R. Dunbrack Jr. R. L. Levy R. M. Conformational Analysis of the DFG-Out Kinase Motif and Biochemical Profiling of Structurally Validated Type II Inhibitors. J. Med. Chem. 2015;58(1):466–479. doi: 10.1021/jm501603h. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit46] Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 2016;103:26–48. doi: 10.1016/j.phrs.2015.10.021. [DOI] [PubMed] [Google Scholar]

[cit47] Martinez R., Defnet A. and Shapiro P., Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors, in Next Generation Kinase Inhibitors: Moving beyond the ATP Binding/Catalytic Sites, ed. P. Shapiro, Springer International Publishing, Cham, 2020, pp. 29–59 [Google Scholar]

[cit48] Łukasik P. Baranowska-Bosiacka I. Kulczycka K. Gutowska I. Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action. Int. J. Mol. Sci. 2021;22(6):2806. doi: 10.3390/ijms22062806. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit49] Gavrin L. K. Saiah E. Approaches to discover non-ATP site kinase inhibitors. MedChemComm. 2013;4(1):41–51. doi: 10.1039/C2MD20180A. [DOI] [Google Scholar]

[cit50] Lee P. Y. Yeoh Y. Low T. Y. A recent update on small-molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry-based proteomic analysis. FEBS J. 2023;290(11):2845–2864. doi: 10.1111/febs.16442. [DOI] [PubMed] [Google Scholar]

[cit51] Lee S. Kim J. Jo J. Chang J. W. Sim J. Yun H. Recent advances in development of hetero-bivalent kinase inhibitors. Eur. J. Med. Chem. 2021;216:113318. doi: 10.1016/j.ejmech.2021.113318. [DOI] [PubMed] [Google Scholar]

[cit52] Zhao Z. Liu Q. Bliven S. Xie L. Bourne P. E. Determining Cysteines Available for Covalent Inhibition Across the Human Kinome. J. Med. Chem. 2017;60(7):2879–2889. doi: 10.1021/acs.jmedchem.6b01815. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit53] Eshaq A. M. Flanagan T. W. Hassan S. Y. Al Asheikh S. A. Al-Amoudi W. A. Santourlidis S. Hassan S. L. Alamodi M. O. Bendhack M. L. Alamodi M. O. Haikel Y. Megahed M. Hassan M. Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance. Cancers. 2024;16(15):2754. doi: 10.3390/cancers16152754. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit54] Qi Y. Deng S. M. Wang K. S. Receptor tyrosine kinases in breast cancer treatment: unraveling the potential. Am. J. Cancer Res. 2024;14(9):4172–4196. doi: 10.62347/KIVS3169. https://dx.doi.org/10.62347/kivs3169 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit55] Maruyama I. N. Mechanisms of activation of receptor tyrosine kinases: monomers or dimers. Cells. 2014;3(2):304–330. doi: 10.3390/cells3020304. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit56] Montor W. R. Salas A. R. O. S. E. Melo F. H. Md. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol. Cancer. 2018;17(1):55. doi: 10.1186/s12943-018-0792-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit57] Hubbard S. R. Miller W. T. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol. 2007;19(2):117–123. doi: 10.1016/j.ceb.2007.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit58] Aref M. M. A. Abdallah A. E. Dahab M. A. Mohamed A. A. Celik I. Bawazir W. A. Mansoure A. A. Alnami A. T. Abdelhamed M. N. El-Zahabi M. A. Design, synthesis, anticancer evaluation, biological screening, and computational study of novel 6,7-dimethoxyquinazoline derivatives as VEGFR-2 inhibitors and apoptotic inducers. Eur. J. Med. Chem. 2026;301:118187. doi: 10.1016/j.ejmech.2025.118187. [DOI] [PubMed] [Google Scholar]

[cit59] Xuhong J. C. Qi X. W. Zhang Y. Jiang J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am. J. Cancer Res. 2019;9(10):2103–2119. [PMC free article] [PubMed] [Google Scholar]

[cit60] Sun K. Wang X. Zhang H. Lin G. Jiang R. Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer. Cancer Control. 2024;31:10732748241278039. doi: 10.1177/10732748241278039. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit61] Shyam S. S. Sharma U. C. Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduction Targeted Ther. 2023;8(1):262. doi: 10.1038/s41392-023-01469-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit62] Shyam Sunder S. Sharma U. C. Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduction Targeted Ther. 2023;8(1):262. doi: 10.1038/s41392-023-01469-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit63] Green J. R. Mahalingaiah P. K. S. Gopalakrishnan S. M. Liguori M. J. Mittelstadt S. W. Blomme E. A. G. Van Vleet T. R. Off-target pharmacological activity at various kinases: Potential functional and pathological side effects. J. Pharmacol. Toxicol. Methods. 2023;123:107468. doi: 10.1016/j.vascn.2023.107468. [DOI] [PubMed] [Google Scholar]

[cit64] Jin Y. Xu Z. Yan H. He Q. Yang X. Luo P. A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors. Front. Pharmacol. 2020;11:891. doi: 10.3389/fphar.2020.00891. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit65] Li J. Gong C. Zhou H. Liu J. Xia X. Ha W. Jiang Y. Liu Q. Xiong H. Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives. Int. J. Mol. Sci. 2024;25(10):5489. doi: 10.3390/ijms25105489. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit66] Shrestha S. Bendzunas G. Kannan N. Protein kinase inhibitor selectivity “hinges” on evolution. Structure. 2022;30(12):1561–1563. doi: 10.1016/j.str.2022.11.004. [DOI] [PubMed] [Google Scholar]

[cit67] Li Y. Fu R. Jiang T. Duan D. Wu Y. Li C. Li Z. Ni R. Li L. Liu Y. Mechanism of Lethal Skin Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors and Related Treatment Strategies. Front. Oncol. 2022;12:804212. doi: 10.3389/fonc.2022.804212. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit68] Dan H. Jiang Q. Jia X. Qi G. Zong D. Li Z. Dermatologic toxicities in epidermal growth factor receptor: a comprehensive pharmacovigilance study from 2013 to 2023. Front. Med. 2024:10–2023. doi: 10.3389/fmed.2023.1283807. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit69] Raja S. R. Khan J. Ibahim M. J. Muhamad M. Bowen J. Wan M. Zain W. N. I. Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review. BioMed Res. Int. 2022;2022:4165808. doi: 10.1155/2022/4165808. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit70] Arter C. Trask L. Ward S. Yeoh S. Bayliss R. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. J. Biol. Chem. 2022;298(8) doi: 10.1016/j.jbc.2022.102247. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit71] Xing L. Klug-Mcleod J. Rai B. Lunney E. A. Kinase hinge binding scaffolds and their hydrogen bond patterns. Bioorg. Med. Chem. 2015;23(19):6520–6527. doi: 10.1016/j.bmc.2015.08.006. [DOI] [PubMed] [Google Scholar]

[cit72] Brauer N. R. Kempen A. L. Hernandez D. Sintim H. O. Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors. Eur. J. Med. Chem. 2024;275:116540. doi: 10.1016/j.ejmech.2024.116540. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit73] Reinecke M. Brear P. Vornholz L. Berger B.-T. Seefried F. Wilhelm S. Samaras P. Gyenis L. Litchfield D. W. Médard G. Müller S. Ruland J. Hyvönen M. Wilhelm M. Kuster B. Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors. Nat. Chem. Biol. 2024;20(5):577–585. doi: 10.1038/s41589-023-01459-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit74] Reynders M. Chaikuad A. Berger B. T. Bauer K. Koch P. Laufer S. Knapp S. Trauner D. Controlling the Covalent Reactivity of a Kinase Inhibitor with Light. Angew. Chem., Int. Ed. Engl. 2021;60(37):20178–20183. doi: 10.1002/anie.202103767. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit75] Montaño J. L. Wang B. J. Volk R. F. Warrington S. E. Garda V. G. Hofmann K. L. Chen L. C. Zaro B. W. Improved Electrophile Design for Exquisite Covalent Molecule Selectivity. ACS Chem. Biol. 2022;17(6):1440–1449. doi: 10.1021/acschembio.1c00980. [DOI] [PubMed] [Google Scholar]

[cit76] Békés M. Langley D. R. Crews C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discovery. 2022;21(3):181–200. doi: 10.1038/s41573-021-00371-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit77] Yu F. Cai M. Shao L. Zhang J. Targeting Protein Kinases Degradation by PROTACs. Front. Chem. 2021:9–2021. doi: 10.3389/fchem.2021.679120. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit78] Broekman F. Giovannetti E. Peters G. J. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J. Clin. Oncol. 2011;2(2):80–93. doi: 10.5306/wjco.v2.i2.80. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit79] Knight Z. A. Lin H. Shokat K. M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer. 2010;10(2):130–137. doi: 10.1038/nrc2787. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit80] Sirhan Z. Thyagarajan A. Sahu R. P. The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer. Mil. Med. Res. 2022;9(1):39. doi: 10.1186/s40779-022-00401-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit81] Gutierrez C. Schiff R. HER2: biology, detection, and clinical implications. Arch. Pathol. Lab. Med. 2011;135(1):55–62. doi: 10.5858/2010-0454-rar.1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit82] Jaradat S. K. Ayoub N. M. Al Sharie A. H. Aldaod J. M. Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer. Technol. Cancer Res. Treat. 2024;23:15330338241234780. doi: 10.1177/15330338241234780. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit83] Ou X. Gao G. Habaz I. A. Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm. 2024;5(9):e694. doi: 10.1002/mco2.694. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit84] Yang Y. Li S. Wang Y. Zhao Y. Li Q. Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective. Signal Transduction Targeted Ther. 2022;7(1):329. doi: 10.1038/s41392-022-01168-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit85] Marín A. Mamun A. A. Patel H. Akamatsu H. Ye D. Sudhan D. R. Eli L. Marcelain K. Brown B. P. Meiler J. Arteaga C. L. Hanker A. B. Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer. Cancer Res. 2023;83(18):3145–3158. doi: 10.1158/0008-5472.CAN-22-3617. https://dx.doi.org/10.1158/0008-5472.Can-22-3617 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit86] Lu J. Zhou K. Yin X. Xu H. Ma B. Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer. Comput. Biol. Chem. 2019;78:290–296. doi: 10.1016/j.compbiolchem.2018.12.007. [DOI] [PubMed] [Google Scholar]

[cit87] Kumar N. Ehsan S. Banerjee S. Fernandez P. C. Lhuilier I. Neuner J. Friebel-Klingner T. Fayanju O. M. Nair B. Niinuma S. A. Nampoothiri S. McCarthy A. M. The unique risk factor profile of triple-negative breast cancer: a comprehensive meta-analysis. J. Natl. Cancer Inst. 2024;116(8):1210–1219. doi: 10.1093/jnci/djae056. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit88] Hirotsu Y. Nakagomi H. Amemiya K. Oyama T. Inoue M. Mochizuki H. Omata M. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med. Oncol. 2016;34(1):3. doi: 10.1007/s12032-016-0857-2. [DOI] [PubMed] [Google Scholar]

[cit89] Xu X. De A. C. Burke K. A. Nardone A. Hu H. Qin L. Veeraraghavan J. Sethunath V. Heiser L. M. Wang N. Ng C. K. Y. Chen E. S. Renwick A. Wang T. Nanda S. Shea M. Mitchell T. Rajendran M. Waters I. Zabransky D. J. Scott K. L. Gutierrez C. Nagi C. Geyer F. C. Chamness G. C. Park B. H. Shaw C. A. Hilsenbeck S. G. Rimawi M. F. Gray J. W. Weigelt B. Reis-Filho J. S. Osborne C. K. Schiff R. HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2(+) Breast Cancer. Clin. Cancer Res. 2017;23(17):5123–5134. doi: 10.1158/1078-0432.CCR-16-2191. https://dx.doi.org/10.1158/1078-0432.Ccr-16-2191 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit90] Wu Z. Wang J. You F. Li X. Xiao C. The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer. Front. Pharmacol. 2023;14 doi: 10.3389/fphar.2023.1142087. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit91] Chumsri S. Sperinde J. Liu H. Gligorov J. Spano J. P. Antoine M. Moreno Aspitia A. Tan W. Winslow J. Petropoulos C. J. Chenna A. Bates M. Weidler J. M. Huang W. Dueck A. Perez E. A. High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance) Clin. Cancer Res. 2018;24(13):3053–3058. doi: 10.1158/1078-0432.CCR-17-1864. https://dx.doi.org/10.1158/1078-0432.Ccr-17-1864 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit92] Jaradat S. K. Ayoub N. M. Al Sharie A. H. Aldaod J. M. Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer. Technol. Cancer Res. Treat. 2024;23:15330338241234780. doi: 10.1177/15330338241234780. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit93] Blangé D. Stroes C. I. Derks S. Bijlsma M. F. van Laarhoven H. W. M. Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review. Cancer Treat. Rev. 2022;108:102418. doi: 10.1016/j.ctrv.2022.102418. [DOI] [PubMed] [Google Scholar]

[cit94] Ahmed M. E. David A. G. An overview of resistance to Human epidermal growth factor receptor 2 (Her2) targeted therapies in breast cancer. Cancer Drug Resist. 2022;5(2):472–486. doi: 10.20517/cdr.2022.09. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit95] Stuhlmiller Timothy J. Miller S. M. Zawistowski Jon S. Nakamura K. Beltran Adriana S. Duncan J. S. Angus Steven P. Collins Kyla A. L. Granger Deborah A. Reuther Rachel A. Graves Lee M. Gomez Shawn M. Kuan P.-F. Parker J. S. Chen X. Sciaky N. Carey Lisa A. Earp H. S. Jin J. Johnson Gary L. Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains. Cell Rep. 2015;11(3):390–404. doi: 10.1016/j.celrep.2015.03.037. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit96] Duncan J. S. Whittle Martin C. Nakamura K. Abell Amy N. Midland Alicia A. Zawistowski Jon S. Johnson Nancy L. Granger Deborah A. Jordan Nicole V. Darr David B. Usary J. Kuan P.-F. Smalley David M. Major B. He X. Hoadley Katherine A. Zhou B. Sharpless Norman E. Perou Charles M. Kim W. Y. Gomez Shawn M. Chen X. Jin J. Frye Stephen V. Earp H. S. Graves Lee M. Johnson G. L. Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer. Cell. 2012;149(2):307–321. doi: 10.1016/j.cell.2012.02.053. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit97] Johnson G. L. Stuhlmiller T. J. Angus S. P. Zawistowski J. S. Graves L. M. Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF–MEK–ERK Pathway in Cancer. Clin. Cancer Res. 2014;20(10):2516–2522. doi: 10.1158/1078-0432.CCR-13-1081. https://dx.doi.org/10.1158/1078-0432.Ccr-13-1081 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit98] Li X. Huang X. Chang M. Lin R. Zhang J. Lu Y. Updates on altered signaling pathways in tumor drug resistance. Visualized Cancer Med. 2024;5:6. doi: 10.1051/vcm/2024007. [DOI] [Google Scholar]

[cit99] Young Hee C. Ai-Ming Y. ABC Transporters in Multidrug Resistance and Pharmacokinetics, and Strategies for Drug Development. Curr. Pharm. Des. 2014;20(5):793–807. doi: 10.2174/138161282005140214165212. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit100] Wang Y. Tu M.-J. Yu A.-M. Efflux ABC transporters in drug disposition and their posttranscriptional gene regulation by microRNAs. Front. Pharmacol. 2024;15 doi: 10.3389/fphar.2024.1423416. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit101] He J. Qiu Z. Fan J. Xie X. Sheng Q. Sui X. Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies. Signal Transduction Targeted Ther. 2024;9(1):209. doi: 10.1038/s41392-024-01891-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit102] Bhat G. R. Sethi I. Sadida H. Q. Rah B. Mir R. Algehainy N. Albalawi I. A. Masoodi T. Subbaraj G. K. Jamal F. Singh M. Kumar R. Macha M. A. Uddin S. Akil A. S. A.-S. Haris M. Bhat A. A. Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev. 2024;43(1):197–228. doi: 10.1007/s10555-024-10172-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit103] Liu S. Jiang A. Tang F. Duan M. Li B. Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment. Mol. Cancer. 2025;24(1):150. doi: 10.1186/s12943-025-02323-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit104] Emmons M. F. Faião-Flores F. Smalley K. S. M. The role of phenotypic plasticity in the escape of cancer cells from targeted therapy. Biochem. Pharmacol. 2016;122:1–9. doi: 10.1016/j.bcp.2016.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit105] Baghban R. Roshangar L. Jahanban-Esfahlan R. Seidi K. Ebrahimi-Kalan A. Jaymand M. Kolahian S. Javaheri T. Zare P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020;18(1):59. doi: 10.1186/s12964-020-0530-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit106] Khalaf K. Hana D. Chou J. T.-T. Singh C. Mackiewicz A. Kaczmarek M. Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front. Immunol. 2021;12 doi: 10.3389/fimmu.2021.656364. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit107] Harry J. A. Ormiston M. L. Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer. Front. Oncol. 2021;11 doi: 10.3389/fonc.2021.772305. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit108] Murphy J. M. Rodriguez Y. A. R. Jeong K. Ahn E. E. Lim S. S. Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp. Mol. Med. 2020;52(6):877–886. doi: 10.1038/s12276-020-0447-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit109] Korkaya H. Liu S. Wicha M. S. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest. 2011;121(10):3804–3809. doi: 10.1172/JCI57099. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit110] Schlam I. Swain S. M. HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now. npj Breast Cancer. 2021;7(1):56. doi: 10.1038/s41523-021-00265-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit111] Cremers C. G. Nguyen L. K. Network rewiring, adaptive resistance and combating strategies in breast cancer. Cancer Drug Resist. 2019;2(4):1106–1126. doi: 10.20517/cdr.2019.60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit112] Iancu G. Serban D. Badiu C. D. Tanasescu C. Tudosie M. S. Tudor C. Costea D. O. Zgura A. Iancu R. Vasile D. Tyrosine kinase inhibitors in breast cancer (Review) Exp. Ther. Med. 2022;23(2):114. doi: 10.3892/etm.2021.11037. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit113] Ou X. Gao G. Habaz I. A. Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm. 2024;5(9):e694. doi: 10.1002/mco2.694. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit114] Wang B. Wu H. Hu C. Wang H. Liu J. Wang W. Liu Q. An overview of kinase downregulators and recent advances in discovery approaches. Signal Transduction Targeted Ther. 2021;6(1):423. doi: 10.1038/s41392-021-00826-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit115] De S. K., An Overview of Protein Kinase Inhibitors, Drug Design and Discovery: Inhibitors of Mitogen-Activated Protein Kinases, Springer Nature Switzerland, Cham, 2024, pp. 1–42 [Google Scholar]

[cit116] Olson D. Taylor J. Willis K. Hensley K. Allred S. Zaval M. Farr L. Thurman R. Jain N. Hein R. Ulrich M. Peterson S. Kulukian A. HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer. Cancer Res. Commun. 2023;3(9):1927–1939. doi: 10.1158/2767-9764.CRC-23-0302. https://dx.doi.org/10.1158/2767-9764.Crc-23-0302 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit117] Reema W.-A. Bolin L. Ann D. T. Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem. Cancer Drug Resist. 2020;3(2):179–198. doi: 10.20517/cdr.2019.92. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit118] Huang F. Han X. Xiao X. Zhou J. Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development. Molecules. 2022;27(22):7728. doi: 10.3390/molecules27227728. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit119] Zhao Z. Bourne P. E. Exploring Extended Warheads toward Developing Cysteine-Targeted Covalent Kinase Inhibitors. J. Chem. Inf. Model. 2024;64(24):9517–9527. doi: 10.1021/acs.jcim.4c00890. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit120] Bálint D. Póti Á. L. Alexa A. Sok P. Albert K. Torda L. Földesi-Nagy D. Csókás D. Turczel G. Imre T. Szarka E. Fekete F. Bento I. Bojtár M. Palkó R. Szabó P. Monostory K. Pápai I. Soós T. Reményi A. Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads. Nat. Commun. 2024;15(1):8606. doi: 10.1038/s41467-024-52573-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit121] Wu P. Clausen M. H. Nielsen T. E. Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015;156:59–68. doi: 10.1016/j.pharmthera.2015.10.002. [DOI] [PubMed] [Google Scholar]

[cit122] Tomuleasa C. Tigu A.-B. Munteanu R. Moldovan C.-S. Kegyes D. Onaciu A. Gulei D. Ghiaur G. Einsele H. Croce C. M. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduction Targeted Ther. 2024;9(1):201. doi: 10.1038/s41392-024-01899-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit123] Luan Y. Li J. Bernatchez J. A. Li R. Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. J. Med. Chem. 2019;62(7):3171–3183. doi: 10.1021/acs.jmedchem.8b00189. [DOI] [PubMed] [Google Scholar]

[cit124] Biersack B. Polat S. Höpfner M. Anticancer properties of chimeric HDAC and kinase inhibitors. Semin. Cancer Biol. 2022;83:472–486. doi: 10.1016/j.semcancer.2020.11.005. [DOI] [PubMed] [Google Scholar]

[cit125] Bass A. K. A. El-Zoghbi M. S. Nageeb E.-S. M. Mohamed M. F. A. Badr M. Abuo-Rahma G. E.-D. A. Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors. Eur. J. Med. Chem. 2021;209:112904. doi: 10.1016/j.ejmech.2020.112904. [DOI] [PubMed] [Google Scholar]

[cit126] Szumilak M. Wiktorowska-Owczarek A. Stanczak A. Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance? Molecules. 2021;26(9):2601. doi: 10.3390/molecules26092601. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit127] He M. Cao C. Ni Z. Liu Y. Song P. Hao S. He Y. Sun X. Rao Y. PROTACs: great opportunities for academia and industry (an update from 2020 to 2021) Signal Transduction Targeted Ther. 2022;7(1):181. doi: 10.1038/s41392-022-00999-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit128] Faryal B. Ul Abideen Z. Irfan M. Ahmed H. Jalilov F. Abduraximova L. Ashraf G. A. Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms. Biomolecules. 2026;16(2):325. doi: 10.3390/biom16020325. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit129] Wang Z. Li Z. Högström J. Inuzuka H. Jing R. Yan P. Hou T. Qi Y. Huang D. Wang J. Wu T. Shi X. Liu B. Muranen T. Zhang D. Wei W. Dual membrane receptor degradation via folate receptor targeting chimera. Nat. Commun. 2025;16(1):8804. doi: 10.1038/s41467-025-63882-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit130] Gumusay O., Vitiello P. P., Wabl C., Corcoran R. B., Bardelli A. and Rugo H. S., Strategic Combinations to Prevent and Overcome Resistance to Targeted Therapies in Oncology, American Society of Clinical Oncology Educational Book, 2020, vol. 40, pp. e292–e308, 10.1200/edbk_280845. PubMed PMID: 32453634 [DOI] [PubMed] [Google Scholar]

[cit131] Rexer B. N. Arteaga C. L. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit. Rev. Oncog. 2012;17(1):1–16. doi: 10.1615/CritRevOncog.v17.i1.20. https://dx.doi.org/10.1615/critrevoncog.v17.i1.20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit132] Wu X. Yang H. Yu X. Qin J.-J. Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies. Front. Pharmacol. 2022;13 doi: 10.3389/fphar.2022.1012552. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit133] Nikanjam M. Liu S. Yang J. Kurzrock R. Dosing Three-Drug Combinations That Include Targeted Anti-Cancer Agents: Analysis of 37,763 Patients. Oncologist. 2017;22(5):576–584. doi: 10.1634/theoncologist.2016-0357. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit134] Rosell R. Karachaliou N. Morales-Espinosa D. Costa C. Molina M. A. Sansano I. Gasco A. Viteri S. Massuti B. Wei J. Cao M. G. Bueno A. M. Adaptive resistance to targeted therapies in cancer. Transl. Lung Cancer Res. 2013;2(3):152–159. doi: 10.3978/j.issn.2218-6751.2012.12.08. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit135] Schlam I. Tarantino P. Tolaney S. M. Overcoming Resistance to HER2-Directed Therapies in Breast Cancer. Cancers. 2022;14(16):3996. doi: 10.3390/cancers14163996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit136] Tan Y. Q. Chiou Y.-S. Guo H. Zhang S. Huang X. Dukanya D. Kumar A. M. Basappa S. Liu S. Zhu T. Basappa B. Pandey V. Lobie P. E. Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer. npj Precis. Oncol. 2024;8(1):8. doi: 10.1038/s41698-023-00489-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit137] Butti R. Das S. Gunasekaran V. P. Yadav A. S. Kumar D. Kundu G. C. Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges. Mol. Cancer. 2018;17(1):34. doi: 10.1186/s12943-018-0797-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit138] Mizuno T. Sakai T. Tanabe K. Umemura T. Goto N. Ohtsu F. Visualization of Kinase Inhibition-Related Adverse Events Using the Japanese Adverse Drug Event Report Database. Drugs Real World Outcomes. 2021;8(2):197–206. doi: 10.1007/s40801-021-00235-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit139] Li Y. Fu R. Jiang T. Duan D. Wu Y. Li C. Li Z. Ni R. Li L. Liu Y. Mechanism of Lethal Skin Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors and Related Treatment Strategies. Front. Oncol. 2022;12 doi: 10.3389/fonc.2022.804212. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit140] Tao G. Chityala P. K. Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management. Toxicol. Res. 2021;10(3):476–486. doi: 10.1093/toxres/tfab026. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit141] Recuero J. K. Fitz J. R. Pereira A. A. Bonamigo R. R. EGFR inhibitors: clinical aspects, risk factors and biomarkers for acneiform eruptions and other mucosal and cutaneous adverse effects. An. Bras. Dermatol. 2023;98(4):429–439. doi: 10.1016/j.abd.2022.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit142] Le Du F. Diéras V. Curigliano G. The role of tyrosine kinase inhibitors in the treatment of HER2+ metastatic breast cancer. Eur. J. Cancer. 2021;154:175–189. doi: 10.1016/j.ejca.2021.06.026. [DOI] [PubMed] [Google Scholar]

[cit143] Diabetes NIo, Digestive, Diseases K. Lapatinib, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2019, Available from: https://www.ncbi.nlm.nih.gov/books/NBK547971/ [Google Scholar]

[cit144] Diabetes NIo, Digestive, Diseases K. Tucatinib, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2023, Available from: https://www.ncbi.nlm.nih.gov/books/NBK595112/ [Google Scholar]

[cit145] Towles J. K. Clark R. N. Wahlin M. D. Uttamsingh V. Rettie A. E. Jackson K. D. Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib. Drug Metab. Dispos. 2016;44(10):1584–1597. doi: 10.1124/dmd.116.070839. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit146] Hardy K. D. Wahlin M. D. Papageorgiou I. Unadkat J. D. Rettie A. E. Nelson S. D. Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab. Dispos. 2014;42(1):162–171. doi: 10.1124/dmd.113.054817. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit147] Kulukian A. Lee P. Taylor J. Rosler R. de Vries P. Watson D. Forero-Torres A. Peterson S. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol. Cancer Ther. 2020;19(4):976–987. doi: 10.1158/1535-7163.MCT-19-0873. https://dx.doi.org/10.1158/1535-7163.Mct-19-0873 [DOI] [PubMed] [Google Scholar]

[cit148] Saran C. Sundqvist L. Ho H. Niskanen J. Honkakoski P. Brouwer K. L. R. Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors. J. Pharmacol. Exp. Ther. 2022;380(2):114–125. doi: 10.1124/jpet.121.000828. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit149] Saran C. Brouwer K. L. R. Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity. Toxicol. Pathol. 2023;51(7–8):405–413. doi: 10.1177/01926233231212255. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit150] Chen M. Borlak J. Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1):388–396. doi: 10.1002/hep.26208. [DOI] [PubMed] [Google Scholar]

[cit151] McEuen K. Borlak J. Tong W. Chen M. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury. Int. J. Mol. Sci. 2017;18(7):1335. doi: 10.3390/ijms18071335. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit152] Viganò M. La Milia M. Grassini M. V. Pugliese N. De Giorgio M. Fagiuoli S. Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer. Cancers. 2023;15(6):1766. doi: 10.3390/cancers15061766. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit153] Di Martino R. M. C. Maxwell B. D. Pirali T. Deuterium in drug discovery: progress, opportunities and challenges. Nat. Rev. Drug Discovery. 2023;22(7):562–584. doi: 10.1038/s41573-023-00703-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit154] Xu V. Ahmed B. Boleslav B. Mager D. E. Sparreboom A. Sprowl J. A. Huang K. M. Insights and perspectives into the etiology of TKI-induced cardiotoxicity. ASPET Discovery. 2026;2:100025. doi: 10.1016/j.aspetd.2026.100025. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit155] Bæk Møller N. Budolfsen C. Grimm D. Krüger M. Infanger M. Wehland M. Magnusson N. E. Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment. Int. J. Mol. Sci. 2019;20(19):4712. doi: 10.3390/ijms20194712. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit156] Jha P. K. Nakano T. Itto L. Y. U. Barbeiro M. C. Lupieri A. Aikawa E. Aikawa M. Vascular inflammation in chronic kidney disease: the role of uremic toxins in macrophage activation. Front. Cardiovasc. Med. 2025;12 doi: 10.3389/fcvm.2025.1574489. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit157] Baldi S. Long N. Ma S. Liu L. Al-Danakh A. Yang Q. Deng X. Xie J. Tang H. Advancements in Protein Kinase Inhibitors: From Discovery to Clinical Applications. Research. 2025;8:0747. doi: 10.34133/research.0747. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit158] Xerxa E. Laufkötter O. Bajorath J. Systematic Analysis of Covalent and Allosteric Protein Kinase Inhibitors. Molecules. 2023;28(15):5805. doi: 10.3390/molecules28155805. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit159] Wang X. DeFilippis R. A. Yan W. Shah N. P. Li H.-y. Overcoming Secondary Mutations of Type II Kinase Inhibitors. J. Med. Chem. 2024;67(12):9776–9788. doi: 10.1021/acs.jmedchem.3c01629. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit160] Treiber D. K. Shah Neil P. Ins and Outs of Kinase DFG Motifs. Chem. Biol. 2013;20(6):745–746. doi: 10.1016/j.chembiol.2013.06.001. [DOI] [PubMed] [Google Scholar]

[cit161] Bradshaw J. M. McFarland J. M. Paavilainen V. O. Bisconte A. Tam D. Phan V. T. Romanov S. Finkle D. Shu J. Patel V. Ton T. Li X. Loughhead D. G. Nunn P. A. Karr D. E. Gerritsen M. E. Funk J. O. Owens T. D. Verner E. Brameld K. A. Hill R. J. Goldstein D. M. Taunton J. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 2015;11(7):525–531. doi: 10.1038/nchembio.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit162] Kenneth K. H. David M. T. Adam R. R. Michelle R. A. Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery. Curr. Top. Med. Chem. 2017;17(1):4–15. doi: 10.2174/1568026616666160719163839. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit163] Lai A. C. Crews C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discovery. 2017;16(2):101–114. doi: 10.1038/nrd.2016.211. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit164] Kossakowski K. Cherniienko A. Zaprutko L. Pawełczyk A. FDA-approved kinase inhibitors in PROTAC design, development and synthesis. J. Enzyme Inhib. Med. Chem. 2025;40(1):2542357. doi: 10.1080/14756366.2025.2542357. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit165] Steelman L. S. Chappell W. H. Abrams S. L. Kempf R. C. Long J. Laidler P. Mijatovic S. Maksimovic-Ivanic D. Stivala F. Mazzarino M. C. Donia M. Fagone P. Malaponte G. Nicoletti F. Libra M. Milella M. Tafuri A. Bonati A. Bäsecke J. Cocco L. Evangelisti C. Martelli A. M. Montalto G. Cervello M. McCubrey J. A. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 2011;3(3):192–222. doi: 10.18632/aging.100296. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit166] Guo Y. J. Pan W. W. Liu S. B. Shen Z. F. Xu Y. Hu L. L. ERK/MAPK signalling pathway and tumorigenesis (Review) Exp. Ther. Med. 2020;19(3):1997–2007. doi: 10.3892/etm.2020.8454. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit167] Bousoik E. Montazeri Aliabadi H. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway. Front. Oncol. 2018;8:287. doi: 10.3389/fonc.2018.00287. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit168] Wu X. Yang H. Yu X. Qin J. J. Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies. Front. Pharmacol. 2022;13:1012552. doi: 10.3389/fphar.2022.1012552. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit169] Tang Q. Peng T. Hu J. Zhang T. Chen P. Chen D. Wang Y. Chen L. Tong L. Chen Y. Xie H. Liang G. Discovery of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine as an effective molecular skeleton to develop reversible/irreversible pan-HER inhibitors. Eur. J. Med. Chem. 2022;233:114249. doi: 10.1016/j.ejmech.2022.114249. [DOI] [PubMed] [Google Scholar]

[cit170] Sever B. Otsuka M. Fujita M. Ciftci H. Design, Synthesis, and Anticancer Evaluation of New Small-Molecule EGFR Inhibitors Targeting NSCLC and Breast Cancer. Int. J. Mol. Sci. 2025;26(15):7065. doi: 10.3390/ijms26157065. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit171] Serag M. I. Tawfik S. S. Badr S. M. I. Eisa H. M. New oxadiazole and pyrazoline derivatives as anti-proliferative agents targeting EGFR-TK: design, synthesis, biological evaluation and molecular docking study. Sci. Rep. 2024;14(1):5474. doi: 10.1038/s41598-024-55046-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit172] Sobh E. A. Khalil N. A. Faggal S. I. Hassan M. S. A. New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF-7 breast cancer cell line. Drug Dev. Res. 2022;83(5):1075–1096. doi: 10.1002/ddr.21934. [DOI] [PubMed] [Google Scholar]

[cit173] Lin S. Zhang X. Yu Z. Huang X. Xu J. Liu Y. Wu L. Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers. Bioorg. Med. Chem. 2022;61:116739. doi: 10.1016/j.bmc.2022.116739. [DOI] [PubMed] [Google Scholar]

[cit174] Bai X. Sun P. Wang X. Long C. Liao S. Dang S. Zhuang S. Du Y. Zhang X. Li N. He K. Zhang Z. Structure and dynamics of the EGFR/HER2 heterodimer. Cell Discovery. 2023;9(1):18. doi: 10.1038/s41421-023-00523-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit175] Swain S. M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug Discovery. 2023;22(2):101–126. doi: 10.1038/s41573-022-00579-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit176] Ishikawa T. Seto M. Banno H. Kawakita Y. Oorui M. Taniguchi T. Ohta Y. Tamura T. Nakayama A. Miki H. Kamiguchi H. Tanaka T. Habuka N. Sogabe S. Yano J. Aertgeerts K. Kamiyama K. Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold. J. Med. Chem. 2011;54(23):8030–8050. doi: 10.1021/jm2008634. [DOI] [PubMed] [Google Scholar]

[cit177] Fedele P. Sanna V. Santoro A. N. Iaia M. L. Fancellu A. Tailoring antiHer2 treatment strategies in breast cancer and beyond. Curr. Probl. Cancer. 2022;46(5):100892. doi: 10.1016/j.currproblcancer.2022.100892. [DOI] [PubMed] [Google Scholar]

[cit178] Wilding B. Woelflingseder L. Baum A. Chylinski K. Vainorius G. Gibson N. Waizenegger I. C. Gerlach D. Augsten M. Spreitzer F. Shirai Y. Ikegami M. Tilandyová S. Scharn D. Pearson M. A. Popow J. Obenauf A. C. Yamamoto N. Kondo S. Opdam F. L. Bruining A. Kohsaka S. Kraut N. Heymach J. V. Solca F. Neumüller R. A. Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers. Cancer Discovery. 2025;15(1):119–138. doi: 10.1158/2159-8290.CD-24-0306. https://dx.doi.org/10.1158/2159-8290.Cd-24-0306 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit179] Hurvitz S. Simonelli M. Yarza R. Berz D. Kitano S. Del Conte G. Acosta Eyzaguirre D. Doger de Speville Uribe B. G. Maier D. Erzen D. Aykut Yazgili S. Curigliano G. Deng T. Yan M. Zhang Q. Wang X. Nakayama I. Shitara K. Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers. Future Oncol. 2025;21(26):3385–3393. doi: 10.1080/14796694.2025.2569553. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit180] Yang B. Yang Y. S. Yang N. Li G. Zhu H. L. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors. Sci. Rep. 2016;6:27571. doi: 10.1038/srep27571. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit181] Ibrahim N. S. M. Kadry H. H. Zaher A. F. Mohamed K. O. Synthesis of novel pyrimido[4,5-b]quinolines as potential anticancer agents and HER2 inhibitors. Chem. Biol. Drug Des. 2023;102(5):996–1013. doi: 10.1111/cbdd.14307. [DOI] [PubMed] [Google Scholar]

[cit182] Mogheith S. M. Allam H. A. Ezzat M. A. F. Khan I. Fandy T. E. Dawud D. Abd Elmageed Z. Y. Albohy A. Ali H. I. Mohamady S. Design, novel one-pot green synthesis, and biological evaluation of pyrazolopyridine-congeners selectively targeting HER2+ breast cancer. Bioorg. Chem. 2025;163:108681. doi: 10.1016/j.bioorg.2025.108681. [DOI] [PubMed] [Google Scholar]

[cit183] Arribas J. Baselga J. Pedersen K. Parra-Palau J. L. p95HER2 and breast cancer. Cancer Res. 2011;71(5):1515–1519. doi: 10.1158/0008-5472.CAN-10-3795. https://dx.doi.org/10.1158/0008-5472.can-10-3795 [DOI] [PubMed] [Google Scholar]

[cit184] Mohan N. Jiang J. Dokmanovic M. Wu W. J. Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers. Antibody Ther. 2018;1(1):13–17. doi: 10.1093/abt/tby003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit185] Schneeweiss A. Chia S. Hegg R. Tausch C. Deb R. Ratnayake J. McNally V. Ross G. Kiermaier A. Cortés J. Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014;16(4):R73. doi: 10.1186/bcr3690. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit186] Musolino A. Ciccolallo L. Panebianco M. Fontana E. Zanoni D. Bozzetti C. Michiara M. Silini E. M. Ardizzoni A. Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study. Cancer. 2011;117(9):1837–1846. doi: 10.1002/cncr.25771. [DOI] [PubMed] [Google Scholar]

[cit187] Elwaie T. A. Abbas S. E. Aly E. I. George R. F. Ali H. Kraiouchkine N. Abdelwahed K. S. Fandy T. E. El Sayed K. A. Abd Elmageed Z. Y. Ali H. I. HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and In Vitro and In Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability. J. Med. Chem. 2020;63(24):15906–15945. doi: 10.1021/acs.jmedchem.0c01647. [DOI] [PubMed] [Google Scholar]

[cit188] Gavriil E. S. Doukatas A. Karampelas T. Myrianthopoulos V. Dimitrakis S. Mikros E. Marakos P. Tamvakopoulos C. Pouli N. Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy. Eur. J. Med. Chem. 2019;176:393–409. doi: 10.1016/j.ejmech.2019.05.029. [DOI] [PubMed] [Google Scholar]

[cit189] Milik S. N. Abdel-Aziz A. K. Lasheen D. S. Serya R. A. T. Minucci S. Abouzid K. A. M. Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors. Eur. J. Med. Chem. 2018;155:316–336. doi: 10.1016/j.ejmech.2018.06.011. [DOI] [PubMed] [Google Scholar]

[cit190] Li D. D. Qin Y. J. Sun J. Li J. R. Fang F. Du Q. R. Qian Y. Gong H. B. Zhu H. L. Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors. PLoS One. 2013;8(8):e69427. doi: 10.1371/journal.pone.0069427. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit191] Fakhry M. M. Mattar A. A. Alsulaimany M. Al-Olayan E. M. Al-Rashood S. T. Abdel-Aziz H. A. New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study. Molecules. 2023;28(21):7455. doi: 10.3390/molecules28217455. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit192] Gomaa H. A. M. Shaker M. E. Alzarea S. I. Alsahli T. G. Alanazi A. S. Mohamed F. A. M. Alanazi M. N. Abou-Zied H. A. Abdelmoez A. Brase S. Youssif B. G. M. Maghraby M. T. E. Design, synthesis, and apoptotic antiproliferative efficacy of new quinazoline/1,3,4-oxadiazole-2-thione derived EGFR/HER-2 dual inhibitors with anti-breast cancer activity. RSC Med. Chem. 2025;16(9):4297–4315. doi: 10.1039/D5MD00454C. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit193] Salem I. M. El-Sabbagh O. I. Mostafa S. M. Salama I. Al-Awadh M. A. Alkhilaiwi F. A. Yonbawi A. R. Binothman N. Hayallah A. M. Ibrahim T. S. Exploitation of novel pyrazolo[3,4-d]pyrimidine scaffold tethered to thiazole as potential EGFR/HER2 dual kinase inhibitor to overcome lapatinib resistant breast cancer: Design, synthesis, in silico docking and molecular dynamic simulation. Bioorg. Chem. 2025;163:108671. doi: 10.1016/j.bioorg.2025.108671. [DOI] [PubMed] [Google Scholar]

[cit194] Al-Wahaibi L. H. El-Sheref E. M. Tawfeek H. N. Abou-Zied H. A. Rabea S. M. Bräse S. Youssif B. G. M. Design, synthesis, and biological evaluation of novel quinoline-based EGFR/HER-2 dual-target inhibitors as potential anti-tumor agents. RSC Adv. 2024;14(45):32978–32991. doi: 10.1039/D4RA06394E. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit195] Hao S. Wang J.-h. Hou L. Liang J.-w. Yan J.-h. Niu Y.-f. Li X.-y. Sun Q. Meng F.-h. Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents. Bioorg. Chem. 2024;151:107686. doi: 10.1016/j.bioorg.2024.107686. [DOI] [PubMed] [Google Scholar]

[cit196] Sabry M. A. Ghaly M. A. Maarouf A. R. El-Subbagh H. I. New thiazole-based derivatives as EGFR/HER2 and DHFR inhibitors: Synthesis, molecular modeling simulations and anticancer activity. Eur. J. Med. Chem. 2022;241:114661. doi: 10.1016/j.ejmech.2022.114661. [DOI] [PubMed] [Google Scholar]

[cit197] Wu Z. Wang J. You F. Li X. Xiao C. The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer. Front. Pharmacol. 2023;14:1142087. doi: 10.3389/fphar.2023.1142087. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit198] Cross D. A. E. Ashton S. E. Ghiorghiu S. Eberlein C. Nebhan C. A. Spitzler P. J. Orme J. P. Finlay M. R. V. Ward R. A. Mellor M. J. Hughes G. Rahi A. Jacobs V. N. Brewer M. R. Ichihara E. Sun J. Jin H. Ballard P. Al-Kadhimi K. Rowlinson R. Klinowska T. Richmond G. H. P. Cantarini M. Kim D.-W. Ranson M. R. Pao W. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discovery. 2014;4(9):1046–1061. doi: 10.1158/2159-8290.CD-14-0337. https://dx.doi.org/10.1158/2159-8290.Cd-14-0337 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit199] Liu H.-N. Zhu Y. Chi Y. Zhang Y. Li X. Wen W. Shan L.-S. Wang Y.-T. Dai B. Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy. Bioorg. Chem. 2024;151:107653. doi: 10.1016/j.bioorg.2024.107653. [DOI] [PubMed] [Google Scholar]

[cit200] Das D. Xie L. Wang J. Xu X. Zhang Z. Shi J. Le X. Hong J. Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities - Part 1. Bioorg. Med. Chem. Lett. 2019;29(4):591–596. doi: 10.1016/j.bmcl.2018.12.056. [DOI] [PubMed] [Google Scholar]

[cit201] Yin S. Tang C. Wang B. Zhang Y. Zhou L. Xue L. Zhang C. Design, synthesis and biological evaluation of novel EGFR/HER2 dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1H)-one scaffold. Eur. J. Med. Chem. 2016;120:26–36. doi: 10.1016/j.ejmech.2016.04.072. [DOI] [PubMed] [Google Scholar]

[cit202] Lin S. Li Y. Zheng Y. Luo L. Sun Q. Ge Z. Cheng T. Li R. Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs. Eur. J. Med. Chem. 2017;127:442–458. doi: 10.1016/j.ejmech.2016.12.055. [DOI] [PubMed] [Google Scholar]

[cit203] Mahboobi S. Sellmer A. Winkler M. Eichhorn E. Pongratz H. Ciossek T. Baer T. Maier T. Beckers T. Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity. J. Med. Chem. 2010;53(24):8546–8555. doi: 10.1021/jm100665z. [DOI] [PubMed] [Google Scholar]

[cit204] Chen C. H. Chen M. C. Wang J. C. Tsai A. C. Chen C. S. Liou J. P. Pan S. L. Teng C. M. Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo. Clin. Cancer Res. 2014;20(5):1274–1287. doi: 10.1158/1078-0432.CCR-12-3909. https://dx.doi.org/10.1158/1078-0432.Ccr-12-3909 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit205] Greve G. Schiffmann I. Pfeifer D. Pantic M. Schüler J. Lübbert M. The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells. BMC Cancer. 2015;15:947. doi: 10.1186/s12885-015-1967-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit206] Tanimoto A. Takeuchi S. Arai S. Fukuda K. Yamada T. Roca X. Ong S. T. Yano S. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. Clin. Cancer Res. 2017;23(12):3139–3149. doi: 10.1158/1078-0432.CCR-16-2271. https://dx.doi.org/10.1158/1078-0432.Ccr-16-2271 [DOI] [PubMed] [Google Scholar]

[cit207] Graves L. M. Duncan J. S. Whittle M. C. Johnson G. L. The dynamic nature of the kinome. Biochem. J. 2013;450(1):1–8. doi: 10.1042/BJ20121456. https://dx.doi.org/10.1042/bj20121456 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit208] Qi S.-M. Dong J. Xu Z.-Y. Cheng X.-D. Zhang W.-D. Qin J.-J. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front. Pharmacol. 2021;12:692574. doi: 10.3389/fphar.2021.692574. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit209] Bricelj A. Steinebach C. Kuchta R. Gütschow M. Sosič I. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Front. Chem. 2021;9:707317. doi: 10.3389/fchem.2021.707317. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit210] Burslem G. M. Smith B. E. Lai A. C. Jaime-Figueroa S. McQuaid D. C. Bondeson D. P. Toure M. Dong H. Qian Y. Wang J. Crew A. P. Hines J. Crews C. M. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem. Biol. 2018;25(1):67–77. doi: 10.1016/j.chembiol.2017.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit211] Chaudhari P. J. Nemade A. R. Shirkhedkar A. A. Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents. RSC Adv. 2024;14(45):33384–33417. doi: 10.1039/D4RA05244G. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit212] Yan J. D. Liu Y. Zhang Z. Y. Liu G. Y. Xu J. H. Liu L. Y. Hu Y. M. Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol., Res. Pract. 2015;211(7):539–543. doi: 10.1016/j.prp.2015.04.003. [DOI] [PubMed] [Google Scholar]

[cit213] Hanna P. E. Anumolu R. K. Motwani S. S. Chen K. L. Katz-Agranov N. Green-Lingren O. Yilmam O. A. Jhaveri K. D. Kitchlu A. Kala J. Sise M. E. Gupta S. Risk Factors for Severe Hypertension and Proteinuria After Treatment With Vascular Endothelial Growth Factor Signaling Pathway Inhibitors Among Patients With Cancer. Kidney Int. Rep. 2024;9(6):1897–1902. doi: 10.1016/j.ekir.2024.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit214] Uyl T. J. J. Ngo A. Pratt D. Cortez I. Mathijssen R. H. J. Versmissen J. Danser A. H. J. Mirabito Colafella K. M. Mechanisms of anti-VEGF therapy-induced kidney injury: current insights and future perspectives in combination with immune checkpoint inhibitors. Am. J. Physiol. 2025;329(2):F284–F299. doi: 10.1152/ajprenal.00081.2025. [DOI] [PubMed] [Google Scholar]

[cit215] Lee J. H. Shim J. W. Choi Y. J. Heo K. Yang K. The combination of sorafenib and radiation preferentially inhibits breast cancer stem cells by suppressing HIF-1α expression. Oncol. Rep. 2013;29(3):917–924. doi: 10.3892/or.2013.2228. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit216] Li X. Wu C. Lin X. Cai X. Liu L. Luo G. You Q. Xiang H. Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2. Eur. J. Med. Chem. 2019;161:445–455. doi: 10.1016/j.ejmech.2018.10.045. [DOI] [PubMed] [Google Scholar]

[cit217] Luo G. Li X. Zhang G. Wu C. Tang Z. Liu L. You Q. Xiang H. Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer. Eur. J. Med. Chem. 2017;140:252–273. doi: 10.1016/j.ejmech.2017.09.015. [DOI] [PubMed] [Google Scholar]

[cit218] Elgammal W. E. Elkady H. Mahdy H. A. Elwan A. Husein D. Z. Amin F. G. Alsfouk B. A. Elkaeed E. B. Eissa I. H. Metwaly A. M. 2,3-Dihydro-1,3,4-thiadiazoles as dual B-Raf/VEGFR-2 inhibitors: Design, synthesis, and anti-breast cancer assessment. J. Mol. Struct. 2026;1354:144717. doi: 10.1016/j.molstruc.2025.144717. [DOI] [Google Scholar]

[cit219] Abdelgawad M. A. Hayallah A. M. Bukhari S. N. A. Musa A. Elmowafy M. Abdel-Rahman H. M. Abd El-Gaber M. K. Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold. Pharmaceuticals. 2022;15(11):1416. doi: 10.3390/ph15111416. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit220] Eissa I. H. Elwan A. Al-Qadhi M. A. Husein D. Z. Amin F. G. Alsfouk A. A. Elkaeed E. B. Elkady H. Metwaly A. M. Targeting VEGFR-2 in breast cancer: synthesis and in silico and in vitro characterization of quinoxaline-based inhibitors. RSC Adv. 2025;15(17):12896–12916. doi: 10.1039/D5RA00526D. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit221] El Hamaky N. F. M. Hamdi A. Bayoumi W. A. Elgazar A. A. Nasr M. N. A. Design, synthesis, and biological evaluation of quinazoline–benzohydrazide and quinazoline–benzothiazole hybrids uncovering a dual EGFR/VEGFR-2 inhibitor with pronounced cytotoxic activity against triple-negative breast Cancer. Bioorg. Med. Chem. 2026;133:118515. doi: 10.1016/j.bmc.2025.118515. [DOI] [PubMed] [Google Scholar]

[cit222] Yousef R. G. El-Metwally S. A. Ward M. M. S. A. Alsfouk A. A. Husein D. Z. Soliman O. A. Elkaeed E. B. Elkady H. Metwaly A. M. Eissa I. H. Discovery of new thieno[2,3-d]pyrimidine-based dual VEGFR-2 and EGFR inhibitors for enhanced therapeutic efficacy in breast cancer. J. Mol. Struct. 2025;1341:142586. doi: 10.1016/j.molstruc.2025.142586. [DOI] [Google Scholar]

[cit223] Mahmoud M. A. Mohammed A. F. Salem O. I. A. Almutairi T. M. Bräse S. Youssif B. G. M. Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors. J. Enzyme Inhib. Med. Chem. 2024;39(1):2305856. doi: 10.1080/14756366.2024.2305856. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit224] Al-Wahaibi L. H. Elshamsy A. M. Ali T. F. S. Youssif B. G. M. Bräse S. Abdel-Aziz M. El-Koussi N. A. Design and Synthesis of New Dihydropyrimidine Derivatives with a Cytotoxic Effect as Dual EGFR/VEGFR-2 Inhibitors. ACS Omega. 2024;9(32):34358–34369. doi: 10.1021/acsomega.4c01361. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit225] Peng F. W. Xuan J. Wu T. T. Xue J. Y. Ren Z. W. Liu D. K. Wang X. Q. Chen X. H. Zhang J. W. Xu Y. G. Shi L. Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC. Eur. J. Med. Chem. 2016;109:1–12. doi: 10.1016/j.ejmech.2015.12.033. [DOI] [PubMed] [Google Scholar]

[cit226] Jansson S. Aaltonen K. Bendahl P. O. Falck A. K. Karlsson M. Pietras K. Rydén L. The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res. Treat. 2018;169(2):231–241. doi: 10.1007/s10549-018-4664-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit227] Chen P. H. Chen X. He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim. Biophys. Acta. 2013;1834(10):2176–2186. doi: 10.1016/j.bbapap.2012.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit228] Yang L. Li N. Xue Z. Liu L.-R. Li J. Huang X. Xie X. Zou Y. Tang H. Xie X. Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer. Cell Death Differ. 2020;27(7):2066–2080. doi: 10.1038/s41418-019-0485-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit229] Joglekar-Javadekar M. Van Laere S. Bourne M. Moalwi M. Finetti P. Vermeulen P. B. Birnbaum D. Dirix L. Y. Ueno N. Carter M. Rains J. Ramachandran A. Bertucci F. van Golen K. L. Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC) Neoplasia. 2017;19(7):564–573. doi: 10.1016/j.neo.2017.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit230] Tan L., Wang J. and Xu W., Crystal Structure of PDGFRA T674I in Complex with Crenolanib. Protein Data Bank, 2019, PDB: 6JOI, 10.2210/pdb6joi/pdb [DOI] [Google Scholar]

[cit231] Yao D. Zhou Y. Zhu L. Ouyang L. Zhang J. Jiang Y. Zhao Y. Sun D. Yang S. Yu Y. Wang J. Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer. Eur. J. Med. Chem. 2017;140:155–171. doi: 10.1016/j.ejmech.2017.08.067. [DOI] [PubMed] [Google Scholar]

[cit232] Iweala E. E. J. Amuji D. N. Oluwajembola A. M. Ugbogu E. A. Targeting c-Met in breast cancer: From mechanisms of chemoresistance to novel therapeutic strategies. Curr. Res. Pharmacol. Drug Discovery. 2024;7:100204. doi: 10.1016/j.crphar.2024.100204. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit233] Jeon H.-M. Lee J. MET: roles in epithelial-mesenchymal transition and cancer stemness. Ann. Transl. Med. 2017;5(1):5. doi: 10.21037/atm.2016.12.67. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit234] Ji X. Meng X. He Q. Xiang X. Shi Y. Zhu X. Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling. Int. J. Mol. Sci. 2023;24(1):757. doi: 10.3390/ijms24010757. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit235] Wang Z. Shi Z. Yang S. Niu Z. Shu K. Chen L. Zhi C. Liu F. Huang W. Fan T. Jiang Y. Design and Synthesis of c-Met and HDAC Dual Inhibitors for the Treatment of Breast Cancer. ACS Med. Chem. Lett. 2024;15(9):1516–1525. doi: 10.1021/acsmedchemlett.4c00256. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit236] Sun Z. Li L. Zhai B. Hu M. Huang L. Huang S. Ye L. Kong X. Xu J. Bai J. Yan J. Zhou Q. Hu Z. Zhang Y. Jiang Y. Zhang Y. Qiao Z. Zou Y. Xu Y. Zhu Q. Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression. J. Med. Chem. 2024;67(6):4916–4935. doi: 10.1021/acs.jmedchem.4c00077. [DOI] [PubMed] [Google Scholar]

[cit237] Naguib B. H. Elsebaie H. A. Nafie M. S. Mohamady S. Albujuq N. R. Samir Ayed A. Nada D. Khalil A. F. Hefny S. M. Tawfik H. O. Shaldam M. A. Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents. Bioorg. Chem. 2024;151:107682. doi: 10.1016/j.bioorg.2024.107682. [DOI] [PubMed] [Google Scholar]

[cit238] Francavilla C. O’Brien C. S. Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer. Open Biol. 2022;12(2):210373. doi: 10.1098/rsob.210373. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit239] Sohl C. D. Ryan M. R. Luo B. Frey K. M. Anderson K. S. Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles’ Heel of Targeted Therapy. ACS Chem. Biol. 2015;10(5):1319–1329. doi: 10.1021/acschembio.5b00014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit240] Kalyukina M. Yosaatmadja Y. Middleditch M. J. Patterson A. V. Smaill J. B. Squire C. J. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem. 2019;14(4):494–500. doi: 10.1002/cmdc.201800719. [DOI] [PubMed] [Google Scholar]

[cit241] Guffanti F. Chilà R. Bello E. Zucchetti M. Zangarini M. Ceriani L. Ferrari M. Lupi M. Jacquet-Bescond A. Burbridge M. F. Pierrat M. J. Damia G. In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models. Neoplasia. 2017;19(1):35–42. doi: 10.1016/j.neo.2016.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit242] Hui R. Pearson A. Cortes J. Campbell C. Poirot C. Azim Jr. H. A. Fumagalli D. Lambertini M. Daly F. Arahmani A. Perez-Garcia J. Aftimos P. Bedard P. L. Xuereb L. Scheepers E. D. Vicente M. Goulioti T. Loibl S. Loi S. Pierrat M. J. Turner N. C. Andre F. Curigliano G. Lucitanib for the Treatment of HR(+)/HER2(-) Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study. Clin. Cancer Res. 2020;26(2):354–363. doi: 10.1158/1078-0432.CCR-19-1164. https://dx.doi.org/10.1158/1078-0432.Ccr-19-1164 [DOI] [PubMed] [Google Scholar]

[cit243] Meric-Bernstam F. Bahleda R. Hierro C. Sanson M. Bridgewater J. Arkenau H. T. Tran B. Kelley R. K. Park J. O. Javle M. He Y. Benhadji K. A. Goyal L. Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study. Cancer Discovery. 2022;12(2):402–415. doi: 10.1158/2159-8290.CD-21-0697. https://dx.doi.org/10.1158/2159-8290.Cd-21-0697 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit244] Sootome H. Fujita H. Ito K. Ochiiwa H. Fujioka Y. Ito K. Miura A. Sagara T. Ito S. Ohsawa H. Otsuki S. Funabashi K. Yashiro M. Matsuo K. Yonekura K. Hirai H. Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020;80(22):4986–4997. doi: 10.1158/0008-5472.CAN-19-2568. https://dx.doi.org/10.1158/0008-5472.Can-19-2568 [DOI] [PubMed] [Google Scholar]

[cit245] Chen Z. Tong L.-j. Tang B.-y. Liu H.-y. Wang X. Zhang T. Cao X.-w. Chen Y. Li H.-l. Qian X.-h. Xu Y.-f. Xie H. Ding J. C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis. Acta Pharmacol. Sin. 2019;40(6):823–832. doi: 10.1038/s41401-018-0191-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit246] Ashraf-Uz-Zaman M. Shahi S. Akwii R. Sajib M. S. Farshbaf M. J. Kallem R. R. Putnam W. Wang W. Zhang R. Alvina K. Trippier P. C. Mikelis C. M. German N. A. Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer. Eur. J. Med. Chem. 2021;209:112866. doi: 10.1016/j.ejmech.2020.112866. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit247] Lang L. Teng Y. Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies. Cells. 2019;8(1) doi: 10.3390/cells8010031. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit248] Mo C. Zhang Z. Guise C. P. Li X. Luo J. Tu Z. Xu Y. Patterson A. V. Smaill J. B. Ren X. Lu X. Ding K. 2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors. ACS Med. Chem. Lett. 2017;8(5):543–548. doi: 10.1021/acsmedchemlett.7b00091. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit249] Krämer J. Bar-Or A. Turner T. J. Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat. Rev. Neurol. 2023;19(5):289–304. doi: 10.1038/s41582-023-00800-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit250] Burger J. A. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr. Hematol. Malig. Rep. 2014;9(1):44–49. doi: 10.1007/s11899-013-0188-8. [DOI] [PubMed] [Google Scholar]

[cit251] Wang X. Kokabee L. Kokabee M. Conklin D. S. Bruton's Tyrosine Kinase and Its Isoforms in Cancer. Front. Cell Dev. Biol. 2021;9:668996. doi: 10.3389/fcell.2021.668996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit252] Varikuti S. Singh B. Volpedo G. Ahirwar D. K. Jha B. K. Saljoughian N. Viana A. G. Verma C. Hamza O. Halsey G. Holcomb E. A. Maryala R. J. Oghumu S. Ganju R. K. Satoskar A. R. Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells. Br. J. Cancer. 2020;122(7):1005–1013. doi: 10.1038/s41416-020-0743-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit253] Chen J. Kinoshita T. Sukbuntherng J. Chang B. Y. Elias L. Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth. Mol. Cancer Ther. 2016;15(12):2835–2844. doi: 10.1158/1535-7163.MCT-15-0923. https://dx.doi.org/10.1158/1535-7163.Mct-15-0923 [DOI] [PubMed] [Google Scholar]

[cit254] Dostálová H. Jorda R. Řezníčková E. Kryštof V. Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines. Invest. New Drugs. 2023;41(2):210–219. doi: 10.1007/s10637-023-01346-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit255] Bender A. T. Gardberg A. Pereira A. Johnson T. Wu Y. Grenningloh R. Head J. Morandi F. Haselmayer P. Liu-Bujalski L. Ability of Bruton’s Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling. Mol. Pharmacol. 2017;91(3):208–219. doi: 10.1124/mol.116.107037. [DOI] [PubMed] [Google Scholar]

[cit256] Guo Y. Liu Y. Hu N. Yu D. Zhou C. Shi G. Zhang B. Wei M. Liu J. Luo L. Tang Z. Song H. Guo Y. Liu X. Su D. Zhang S. Song X. Zhou X. Hong Y. Chen S. Cheng Z. Young S. Wei Q. Wang H. Wang Q. Lv L. Wang F. Xu H. Sun H. Xing H. Li N. Zhang W. Wang Z. Liu G. Sun Z. Zhou D. Li W. Liu L. Wang L. Wang Z. Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. J. Med. Chem. 2019;62(17):7923–7940. doi: 10.1021/acs.jmedchem.9b00687. [DOI] [PubMed] [Google Scholar]

[cit257] Sulzmaier F. J. Jean C. Schlaepfer D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer. 2014;14(9):598–610. doi: 10.1038/nrc3792. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit258] Murphy J. M. Rodriguez Y. A. R. Jeong K. Ahn E.-Y. E. Lim S.-T. S. Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp. Mol. Med. 2020;52(6):877–886. doi: 10.1038/s12276-020-0447-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit259] Paul R. Luo M. Mo X. Lu J. Yeo S. K. Guan J.-L. FAK activates AKT-mTOR signaling to promote the growth and progression of MMTV-Wnt1-driven basal-like mammary tumors. Breast Cancer Res. 2020;22(1):59. doi: 10.1186/s13058-020-01298-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit260] Fukami S. Tomioka D. Murakami Y. Honda T. Hatakeyama S. Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo tumor models. BMC Res. Notes. 2019;12(1):347. doi: 10.1186/s13104-019-4389-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit261] Wang L. Ai M. Yu J. Jin L. Wang C. Liu Z. Shu X. Tang Z. Liu K. Luo H. Guan W. Sun X. Ma X. Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells. Eur. J. Med. Chem. 2019;172:154–162. doi: 10.1016/j.ejmech.2019.04.004. [DOI] [PubMed] [Google Scholar]

[cit262] Groendyke B. J. Nabet B. Mohardt M. L. Zhang H. Peng K. Koide E. Coffey C. R. Che J. Scott D. A. Bass A. J. Gray N. S. Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor. ACS Med. Chem. Lett. 2021;12(1):30–38. doi: 10.1021/acsmedchemlett.0c00338. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit263] Portugal C. C. Almeida T. O. Socodato R. Relvas J. B. Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases. FEBS J. 2022;289(24):7760–7775. doi: 10.1111/febs.16197. [DOI] [PubMed] [Google Scholar]

[cit264] Alper O. Bowden E. T. Novel Insights Into c-Src. Curr. Pharm. Des. 2005;11(9):1119–1130. doi: 10.2174/1381612053507576. [DOI] [PubMed] [Google Scholar]

[cit265] Parks E. E. Ceresa B. P. Cell surface epidermal growth factor receptors increase Src and c-Cbl activity and receptor ubiquitylation. J. Biol. Chem. 2014;289(37):25537–25545. doi: 10.1074/jbc.M114.579581. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit266] Chen Z. Oh D. Dubey A. K. Yao M. Yang B. Groves J. T. Sheetz M. EGFR family and Src family kinase interactions: mechanics matters? Curr. Opin. Cell Biol. 2018;51:97–102. doi: 10.1016/j.ceb.2017.12.003. [DOI] [PubMed] [Google Scholar]

[cit267] Campbell E. J. McDuff E. Tatarov O. Tovey S. Brunton V. Cooke T. G. Edwards J. Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer. Br. J. Cancer. 2008;99(11):1769–1774. doi: 10.1038/sj.bjc.6604768. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit268] Zhang S. Huang W. C. Li P. Guo H. Poh S. B. Brady S. W. Xiong Y. Tseng L. M. Li S. H. Ding Z. Sahin A. A. Esteva F. J. Hortobagyi G. N. Yu D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 2011;17(4):461–469. doi: 10.1038/nm.2309. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit269] Fraser C. Dawson J. C. Dowling R. Houston D. R. Weiss J. T. Munro A. F. Muir M. Harrington L. Webster S. P. Frame M. C. Brunton V. G. Patton E. E. Carragher N. O. Unciti-Broceta A. Rapid Discovery and Structure–Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. J. Med. Chem. 2016;59(10):4697–4710. doi: 10.1021/acs.jmedchem.6b00065. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit270] Zou L. Yadav U. P. Marianesan A. B. Kumar R. Singh T. G. Verma A. Alasiri G. Fareed M. Alam P. Sathish E. Huang Y. Design and synthesis of tetrazole tethered quinazoline derivatives via azide-isocyanide cross-coupling reaction: Exploring the utility as anticancer agents via the SRC kinase inhibition in breast cancer. Bioorg. Chem. 2025;164:108844. doi: 10.1016/j.bioorg.2025.108844. [DOI] [PubMed] [Google Scholar]

[cit271] Wang Y. Huang A. Chen L. Sun F. Zhao M. Zhang M. Xie Y. Xu S. Li M. Hong L. Li G. Wang R. Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer. Eur. J. Med. Chem. 2024;264:116009. doi: 10.1016/j.ejmech.2023.116009. [DOI] [PubMed] [Google Scholar]

[cit272] Brandvold K. R. Steffey M. E. Fox C. C. Soellner M. B. Development of a Highly Selective c-Src Kinase Inhibitor. ACS Chem. Biol. 2012;7(8):1393–1398. doi: 10.1021/cb300172e. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit273] Ko K. S. Steffey M. E. Brandvold K. R. Soellner M. B. Development of a chimeric c-Src kinase and HDAC inhibitor. ACS Med. Chem. Lett. 2013;4(8):779–783. doi: 10.1021/ml400175d. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit274] Agashe R. P. Lippman S. M. Kurzrock R. JAK: Not Just Another Kinase. Mol. Cancer Ther. 2022;21(12):1757–1764. doi: 10.1158/1535-7163.MCT-22-0323. https://dx.doi.org/10.1158/1535-7163.Mct-22-0323 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit275] Jin W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition. Cells. 2020;9(1):217. doi: 10.3390/cells9010217. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit276] Moon S. Y. Lee H. Kim S. Hong J. H. Chun S. H. Lee H. Y. Kang K. Kim H. S. Won H. S. Ko Y. H. Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells. BMC Cancer. 2021;21(1):931. doi: 10.1186/s12885-021-08641-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit277] Kim J. W. Gautam J. Kim J. E. Kim J. A. Kang K. W. Inhibition of tumor growth and angiogenesis of tamoxifen-resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor. Oncol. Lett. 2019;17(4):3981–3989. doi: 10.3892/ol.2019.10059. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit278] You K. S. Kim T.-S. Back S. M. Park J.-S. Liu K. Seong Y.-S. Kim D. J. Yi Y. W. JAK2 Inhibition Augments the Anti-Proliferation Effects by AKT and MEK Inhibition in Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2025;26(13):6139. doi: 10.3390/ijms26136139. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit279] Yang E. G. Mustafa N. Tan E. C. Poulsen A. Ramanujulu P. M. Chng W. J. Yen J. J. Dymock B. W. Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines. J. Med. Chem. 2016;59(18):8233–8262. doi: 10.1021/acs.jmedchem.6b00157. [DOI] [PubMed] [Google Scholar]

PERMALINK

Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer

Tamer A Elwaie

Mostafa M A Aref

Hamed I Ali

Abstract

Introduction

Fig. 1. Illustration of the major types of breast cancer. The image categorizes breast cancer into three main subtypes: hormonal-dependent breast cancer (HR+/luminal), HER2+ breast cancer, and triple-negative breast cancer (TNBC/basal). Figure created using BioRender.com.

Kinase inhibitors as targeted treatments for breast cancer

Resistance mechanisms in kinase-targeted therapies in breast cancer treatment

Major kinase-targeted therapeutic strategies in breast cancer

Table 1. Comparative overview of major kinase-targeted therapeutic strategies in breast cancer, highlighting their mechanisms, advantages, limitations, and context-dependent applications across selective, covalent, multitarget, hybrid, degrader-based, and combination approaches.

Toxicity and off-target challenges of breast cancer TKIs

Human epidermal growth factor receptors

Table 2. EGFR inhibitors with the reported anti-breast cancer activity.

HER-2 inhibition

Reversible dual EGFR/HER-2 kinase inhibitors

Table 3. Anti-breast cancer EGFR/HER-2 dual inhibitors.

Irreversible dual EGFR/HER-2 kinase inhibitors

Fig. 6. The rationale for the design of conjugate 31 is to integrate an alkylating moiety (cyclophosphamide) with quinazoline-based EGFR/HER2 inhibitors. The metabolism of cyclophosphamide to its active form and the avoidance of acrolein-induced nephrotoxicity are highlighted.

EGFR/HER-2 & HDAC hybrid inhibitors

Fig. 7. Development of hybrid inhibitors targeting EGFR, HER2, and HDAC: lapatinib was modified to incorporate a hydroxamic acid-based zinc-binding group (ZBG) to inhibit HDAC, affording hybrids 32 and 33.

Lapatinib-based PROTACs induced EGFR/HER2 degradation

Fig. 8. The figure illustrates the mechanism of targeted protein degradation using lapatinib-based PROTACs.

VEGFR inhibitors

Table 4. VEGFR-2 inhibitors targeting BC.

VEGFR-2/HDAC inhibitors

Fig. 10. Design of a dual VEGFR-2 and HDAC inhibitor through pharmacophoric hybridization: vandetanib, a VEGFR-2 inhibitor, and vorinostat, a HDAC inhibitor, were merged to create a hybrid compound (57) with improved dual-targeting potential.

PDGFR kinase inhibitors

Met inhibitors

FGFR inhibitors

Bruton tyrosine kinase (BTK)

Fig. 14. Chemical structures and binding interactions of (a) Ibrutinib (PDB: 5P9J) and (b) Zanubrutinib (PDB: 6J6M) with Bruton's tyrosine kinase (BTK), highlighting detailed molecular interactions and binding site environments.

FAK inhibitors

SRC inhibition

Fig. 16. Design and optimization of a multi-kinase inhibitor (78) to a selective c-Src scaffold (79) with key hinge interactions, compared to reference Src inhibitors dasatinib, bosutinib, and compound 82.

Fig. 17. Hybridization of the BRD4 inhibitor JQ1 and the c-Src inhibitor dasatinib via a tailored linker yields HL403, a dual BRD4/Src inhibitor and potent activity against breast cancer MDA-MB-231 cells.

JAK inhibition

Fig. 19. Pharmacophore-merging strategy combining JAK hinge/solvent-channel motifs (ruxolitinib/pacritinib) with the HDAC zinc-binding group (vorinostat) to yield a dual JAK2/HDAC inhibitor active in BC cells.

Conclusion

Author contributions

Conflicts of interest

Acknowledgments

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Fig. 1. Illustration of the major types of breast cancer. The image categorizes breast cancer into three main subtypes: hormonal-dependent breast cancer (HR⁺/luminal), HER2⁺ breast cancer, and triple-negative breast cancer (TNBC/basal). Figure created using BioRender.com.