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. 2025 Apr 30;17(9):1055–1069. doi: 10.1080/17568919.2025.2498881

The antibreast cancer therapeutic potential of quinazoline hybrids–Part I

Wei Chen a,*, Ruo Wang a,✉,*, Yidan Lin b, Xiaoqiang Wang c, Feili Cai a, Mengbo Lin a, Jiawen Wang d,✉, Hui Zhang a,✉, Min Chen e,✉
PMCID: PMC12091908  PMID: 40304260

ABSTRACT

Breast cancer is the most commonly diagnosed cancer in women and is the leading cause of cancer-related mortality among female patients across the world. Chemotherapy is a critical means for breast cancer therapy, and administration of chemotherapy could reduce the risk of recurrence by approximately one-third in early breast cancer. However, multidrug resistance represents a principal obstacle to effective chemotherapeutic interventions against breast cancer and is an increasing clinical challenge, creating an urgent demand to explore innovative chemotherapeutics to combat this formidable disease. Quinazoline hybrids with structural and mechanistic diversity exhibit excellent activity against breast cancers including drug-resistant forms and have the potential to reduce side effects caused by the corresponding pharmacophores. Notably, lapatinib, a quinazoline-furan-sulfone hybrid, has already been launched for breast cancer therapy. Thus, quinazoline hybrids represent a fertile source for the development of novel chemotherapeutics for clinical deployment in the control and eradication of breast cancer. This review emphasizes the current scenario of quinazoline hybrids with antibreast cancer therapeutic potential and focuses on structure-activity relationships (SARs) and modes of action, developed from 2020 onwards, to facilitate the rational discovery of more effective antibreast cancer candidates.

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This review emphasizes the current landscape of quinazoline hybrids with antibreast cancer therapeutic potential, delves into structure-activity relationships and mechanisms of action developed from 2020 onwards, aiming to facilitate the rational discovery of more effective and less toxic candidates.

KEYWORDS: Quinazoline, hybrid molecules, breast cancer, drug resistance, mechanisms of action

1. Introduction

Breast cancer is a disease in which abnormal breast cells grow out of control and form tumors and can spread to other parts of the body as well as trigger other symptoms [1,2]. Breast cancer is the most prevalent cancer among female, and approximately 99% of breast cancers occur in women [2,3]. Besides being the most common, breast cancer is also the leading cause of cancer-related mortality in women patients globally [3,4]. There were 2.3 million (11.6% of all cancer diagnoses) new cases and 670,000 deaths (6.9% of the total cancer deaths) of invasive breast cancer occurred in 2022 according to the World Health Organization (WHO) estimation [5]. Moreover, the morbidity and mortality of breast cancer have continuously increased over the last three decades, and the numbers will rise to 3.0 million and 1.0 million respectively by 2040 [6].

Based on the immunohistochemical expression of estrogen (ER, >70% invasive breast carcinomas characterized by significantly high ER expression), progesterone (PR, expressed in > 50% of ER + patients) and human epidermal growth factor 2 (HER2, accounts for  ~  20% breast cancer) hormone receptors, breast cancer can be divided into four subtypes: luminal A, luminal B, HER2-positive, and triple-negative subtypes [7,8]. Treatment depends on the subtype and the status of lymph nodes, and chemotherapy is a critical means for breast cancer therapy to prolong survival time and maintain quality of life [9,10]. However, multidrug resistance is a surmountable obstacle for breast cancer therapy, which is mainly caused by over-expression of drug transporters and related enzymes in breast cancer cells [11,12]. Therefore, there is an urgent demand to explore innovative chemotherapeutics to combat this formidable disease.

Quinazolines including quinazolinones mainly act by inhibiting different protein kinases such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-2 (VEGFR-2), B rapidly accelerated fibrosarcoma (BRAF), phosphoinositide 3-kinase (PI3K), and mesenchymal-epithelial transition factor (c-Met), which ultimately suppress the replication and transcription of DNA and thereby impede the tumor growth [13,14]. Moreover, quinazolines have the potential to overcome drug resistance by inhibiting breast cancer resistant proteins [14]. Particularly, quinazoline hybrids as one of the most popular chemical entities to work upon for the development of novel antibreast cancer agents with improved and amazing properties have the potential to conquer drug resistance and reduce side effects caused by the corresponding pharmacophores [15,16]. Moreover, quinazoline-furan-sulfone hybrid lapatinib (Figure 1) could act on EGFR and HER2 and has already been applied in clinics for breast cancer therapy, demonstrating that quinazoline hybrids hold great promise as valuable scaffolds for the development of novel chemotherapeutics for clinical deployment in the control and eradication of breast cancer [17,18]. This review emphasizes the current landscape of quinazoline hybrids, inclusive of quinazoline-sulfone/sulfonate/sulfonamide hybrids, quinazoline-(thio)urea hybrids, quinazoline-indole/pyrrole/furan hybrids, quinazoline-chalcone hybrids, quinazoline-hydroxamic acid hybrids and quinazoline-hydrazone hybrids, with antibreast cancer therapeutic potential, delves into structure-activity relationships (SARs) and mechanisms of action developed from 2020 onwards, aiming to facilitate the rational discovery of more effective and less toxicity candidates.

Figure 1.

Figure 1.

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Structures of quinazoline, quinazolinone and lapatinib.

2. Quinazoline-sulfone/sulfonate/sulfonamide hybrids

The antiproliferative SARs of phenothiazine-containing quinazoline-furan-sulfone hybrids 1 (Figure 2; IC50: 1.03–9.16 µM, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide/MTT assay) against MCF-7, MDA-MB-231 and lapatinib-resistant MDA-MB-231/lapatinib breast cancer cell lines elucidated that (1) extension of the carbon spacer between amide and ester decreased the activity; (2) chloro was more favorable than trifluoromethyl at C-2 position of phenothiazine moiety; (3) replacement of phenothiazine moiety by naphtho[2,3-b]furan-4,9-dione was tolerated, and hybrids 2 (IC50: 1.69–5.82 µM) also exhibited excellent antiproliferative activity against the three breast cancer cell lines [19]. Amongst them, the representative hybrids 1a (IC50: 3.62, 1.54 and 1.03 µM) and 2b (IC50: 13.86, 2.04 and 1.69 µM) were more potent than lapatinib (IC50: 12.62, 5.86 and 29.39 µM) against the tested breast cancer cell lines and displayed low cytotoxicity (IC50: 89.23 and 63.31 µM) towards normal human umbilical vein endothelial cells (HUVEC). In addition, hybrid 1a could reverse lapatinib-mediated resistance of MDA-MB-231 cells by inhibition of cancer cell stemness and the AKT/ERK signaling pathway, block the cell cycle mainly in G2/M phase, induce cell apoptosis, and suppress the invasion and migration of cancer cells through suppressing the Wnt/β-catenin signaling pathway and matrix metalloproteinase 2 (MMP-2) and MMP-9 protein expression. Further studies showed that 100% of the mice in the vehicle group-treated MDA-MB-231/lapatinib cells developed tumors, and 80% of the mice injected with the lapatinib-treated cells developed tumors, while only 10% of the mice injected with the hybrid 1a-treated cells developed tumors at 8 weeks. Thus, hybrid 1a could inhibit drug-resistant breast cancer cell stemness with lower tumor-initiating potential.

Figure 2.

Figure 2.

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Structures of quinazoline-sulfone/sulfonate/sulfonamide hybrids 1–15.

A significant part of quinazoline-sulfone hybrids 3 (IC50: 0.30–2.10 μM, Sulforhodamine B/SRB assay) exhibited potent antiproliferative activity against MCF-7 breast cancer cells [20]. The SARs illustrated that (1) pyrrolidine and morpholine fragments at C-4 position of quinazoline moiety were beneficial for the activity; (2) methoxy group at para-position of phenyl ring was essential for the high activity. In particular, hybrids 3a,b (IC50: 300 and 520 nM) were not inferior to mitomycin (IC50: 500 nM) against breast cancer cells and could serve as lead compounds for further investigations.

Quinazoline-sulfonate hybrids 4 (IC50: 4.60–9.79 μM, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium/MTS assay) were more potent than imatinib (IC50: >25 μM) against MCF-7 breast cancer cells, and the SAR indicated that chloro at C-7 position of quinazoline moiety was favorable to the activity [21]. Moreover, hybrids 4 arrested cycle cell at G2/M phase and were capable of activating the p53-dependent or p53-independent apoptosis pathway and inducing apoptosis via effectors that acted in a caspase-dependent or independent manner.

Quinazolinone-sulfonamide hybrid 5 (IC50: 1.8–271.0 nM) exhibited profound inhibitory effects against PI3Kα/β/γ/δ and showed low human ether-a-go-go related gene (hERG) channel inhibitory activity with a IC50 value of 27.5 μM, indicating its low cardiotoxicity potential [22]. Moreover, hybrid 5 (oral administration) also possessed excellent pharmacokinetic properties in mouse (10 mg/kg) and rat (3.0 mg/kg): peak concentration (Cmax) values were 22,167 and 2327 ng/mL, area under the curve (AUC0-∞) values were 3090 and 2711 h•ng/mL, and bioavailability (F%) values were 59.4% and 46.9%, respectively. In the BT-474 breast cancer xenografted mice model, hybrid 5 (oral administration) could dose-dependently suppress tumor growth by 62.5% (15 mg/kg), 86.0% (30 mg/kg) and 90.7% (40 mg/kg), respectively, which was attributed to inhibition of the PI3Ks downstream critical node of Akt phosphorylation. No substantial alterations in the body weight of the mice were observed prior to and following the application of hybrid 5, revealing the absence of evident toxicity at a dose of 40 mg/kg via oral administration. Taken together, hybrid 5 as an orally active and selective PI3K inhibitor was worthy of further preclinical evaluations for breast cancer therapy.

Quinazolinone-sulfonamide hybrids 6 (IC50: 650 nM, MTT assay) and 7a-f (IC50: 160–820 nM) were highly potent against MCF-7 breast cancer cells, and the antiproliferative activity was 3.0–15.6 times superior to that of sorafenib (IC50: 2.50 µM) [23]. Mechanistically, these hybrids inhibited the cell growth at the G2/M phase through pre-G1 apoptosis in MCF-7 breast cancer cells [24]. Among them, hybrids 6 (IC50: 430 and 150 nM) and 7a (IC50: 270 and 180 nM) were dual inhibitors of EGFR and HER2 and displayed relative low cytotoxicity (IC50: 13.46 and 4.70 µM) toward normal MRC-5 cells.

Quinazolinone-sulfonamide hybrids 8 (IC50: 2.5–74.03 µM, MTT assay) showed higher antiproliferative activity than 5-flurouracil (IC50: 95.63 µM) against MCF-7 breast cancer cells, and the SAR indicated that alkyl group on the phenyl ring improved the activity [25,26]. The most active hybrids 8a,b (IC50: 2.5 and 5.0 µM) were comparable to doxorubicin (IC50: 1.4 µM) against MCF-7 breast cancer cells and could mediate apoptosis and arrest cell cycle growth at G1 phase [25]. Further structural modifications revealed that introduction of iodo into C-6 position of quinazoline moiety was permitted, and hybrids 9a,b (IC50: 97.7 and 178.1 nM, MTT assay) were more potent than sorafenib (IC50: 404 nM) and erlotinib (IC50: 549 nM) against MCF-7 cancer cells [27–29]. Hybrid 9a (IC50: 72.8 and 52.3 nM) as a potent dual inhibitor of EGFRT790M and VEGFR-2 arrested cell cycle at the G2/M phase and induced apoptosis in MCF-7 cells [27]. Incorporation of substituent into sulfonamide moiety was also tolerated, and hybrid 10 (IC50: 8.38 µM, MTT assay) was superior to doxorubicin (IC50: 15.25 µM) against MCF-7 cancer cells [30]. Quinazolinone-sulfonamide hybrids 11a,b (IC50: 6.79 and 7.10 µM, MTT assay) were not inferior to doxorubicin (IC50: 7.67 µM) and sorafenib (IC50: 7.21 µM) against MCF-7 breast cancer cells and were comparable to sorafenib (IC50: 377 and 415 nM vs 588 nM) in terms of inhibition of VEGFR-2 [31]. Quinazolinone-sulfonamide hybrid 12 (IC50: 3.87 µM, MTT assay) was superior to doxorubicin (IC50: 9.34 µM) and erlotinib (IC50: 12.40 µM) against MCF-7 breast cancer cells [32], whereas hybrid 13 (IC50: 3.03 µM, MTT assay) was more active than roscovitine (IC50: 5.26 µM) against MDA-MB-435 breast cancer cells [33,34]. Mechanistically, hybrid 13 could arrest cell cycle at S phase and induce apoptosis [34]. Accordingly, these hybrids were useful scaffolds for the discovery of novel chemotherapeutics for the treatment of breast cancer.

Quinazoline-sulfonamide hybrid 14 (IC50: 2.54 and 4.14 µM, MTT assay) was not inferior to 5-flurouracil (IC50: 2.46 and 6.70 µM) against MCF-7 and T-47D breast cancer cell lines, and the SARs illustrated that (1) fluoro on the phenyl ring was critical for the high activity [35]; (2) thiother at C-2 position of quinazoline moiety was not essential for the activity, and hybrid 15 (concentration that inhibits cell growth by 50%/GI50: 2.14–4.28 µM, MTT assay) showed promising antiproliferative activity against MCF-7, MDA-MB-231, MDA-MB-468, HS 578 T, and T-47D breast cancer cell lines [36]. Besides, hybrid 14 (IC50: 90 nM) exhibited pronounced inhibitory effect against carbonic anhydrase II (CA II) and could arrest the cell cycle at the G2/M phase as well as potentiate early apoptotic and late apoptotic and the necrotic stages.

3. Quinazoline-(thio)urea hybrids

A significant part of quinazoline-urea hybrids 16 (Figure 3; IC50: 1.14–9.29 µM, MTT assay) exhibited promising antiproliferative activity against MCF-7 breast cancer cells, and the SAR demonstrated that fluoro at R2 position of phenyl ring was favorable to the activity [37]. Particularly, hybrids 16a-c (IC50: 3.53, 3.64 and 1.14 µM, respectively) were not inferior to afatinib (IC50: 1.84 µM) and more active than foretinib (IC50: >100 µM) against MCF-7 cancer cells. Moreover, hybrid 16a (IC50: 64.8, 305.4 and 137.4 nM) was a potent EGFRwt, EGFRL858R/T790M, and c-Met inhibitor and could arrest cell cycle at the G2/M phase and induce apoptosis. Hybrid 16a had poor hemolysis at low concentrations, with over 5% hemolysis of 2% sheep blood erythrocytes at 64 μg/mL. No signs of cell damage or necrosis, cell morphology and structure were clear, and no damage in major organs (heart, liver, spleen, lung and kidney) were observed in mouse toxicity experiments at 100 mg/kg of hybrid 16a via oral administration, revealing its good safety profiles.

Figure 3.

Figure 3.

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Structures of quinazoline-(thio)urea hybrids 16–23.

The antiproliferative SAR of quinazoline-urea hybrids 17 (IC50: 2.26->10 µM, MTT assay) against MCF-7 breast cancer cells illustrated that halogen atoms at R2 position were favorable to the activity, and the representative hybrids 17a-c (IC50: 2.26, 3.50 and 4.25 µM) were superior to gefitinib (IC50: 13.87 µM) and NSC-639829 (IC50: 22.60 µM) [38]. In addition, hybrid 17a (IC50: 2.77 µM) was also more potent than gefitinib (IC50: 21.55 µM) and NSC-639829 (IC50: 20.37 µM) against MDA-MB-453 breast cancer cells and displayed relative low cytotoxicity (IC50: 21.03 µM) toward normal L02 cells. Hybrid 17a (IC50: 10.66 nM) also exhibited superior inhibitory activity against EGFR kinases compared to gefitinib (IC50: 25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, hybrid 17a remarkably impeded tubulin polymerization, disrupted the intracellular microtubule network, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration.

Quinazoline-urea hybrids 18 (IC50: 0.2–1.8 µM, CellTiterGlo®3 assay) showed potent antiproliferative activity against MCF-7 breast cancer cells, and the SAR indicated that introduction of substituent into para-position of phenyl ring was beneficial for the activity [39]. Among them, hybrids 18a-c (IC50: 200 nM) were found to be most active against MCF-7 cancer cells and exhibited excellent inhibitory effects against PI3Kα (IC50: 2.4, 0.7 and 3.4 nM) and mTOR (IC50: 58.8, 114 and 95.1 nM). Hybrids 19a,b were highly potent against MCF-7 (IC50: 0.2 and 1.1 µM, MTT assay) and MDA-MB-231 (IC50: 1.0 and 1.7 µM) breast cancer cell lines, and hybrid 19a effectively inhibited the phosphorylation of Akt, mTOR and ribosomal protein S6 kinase (S6K), damaged DNA and stimulated autophagy, depolarized lysosomes, and triggered poly ADP-ribose polymerase 1 (PARP1) cleavage, reactive oxygen species (ROS) production, and cell death [40].

The antiproliferative SARs of quinazoline-urea hybrids 20 (IC50: 2.81–5.68 µM, MTT assay) against MCF-7 breast cancer cells elucidated that (1) 4-chloro-3-trifluoromethyl group on the phenyl ring attached to urea moiety was essential for the high activity; (2) halogen atoms on the phenyl ring at C-4 position of quinazoline motif were favorable to the activity [41]. In particular, hybrids 20a-d (IC50: 2.81–3.95 µM) were comparable to sorafenib (IC50: 3.47 µM) and superior to gefitinib (IC50: 15.68 µM) and erlotinib (IC50: 11.42 µM) against MCF-7 cancer cells. Besides, the most active hybrid 20a (IC50: 17.32 nM) also showed higher inhibitory activity than gefitinib (IC50: 25.42 nM) and erlotinib (IC50: 33.25 nM) in terms of inhibition of EGFR.

SP-96 (21, IC50: 107 nM), a pyrazole-containing quinazoline-urea hybrid, demonstrated pronounced antiproliferative activity against MDA-MB-468 breast cancer cells [42]. SP-96 (IC50: 0.316 nM) also exhibited great inhibitory effect against Aurora B and did not inhibit FMS-like receptor tyrosine kinase-3 (FLT3)/kinase insert domain receptor (KIT), which were important for normal hematopoiesis. Therefore, SP-96 as non-adenosine triphosphate (ATP) competitive inhibitor was worthy of further investigations.

Quinazoline-thiourea hybrids 22a,b (IC50: 4.92 and 7.56 µM, MTT assay) were not inferior to sorafenib (IC50: 7.62 µM) against MCF-7 breast cancer cells, and the SAR indicated that introduction of furan into C-2 position of quinazoline moiety was permitted as evidenced by that hybrid 23 (IC50: 9.71 µM, MTT assay) also exhibited promising antiproliferative activity against MCF-7 cancer cells [43]. Moreover, hybrids 22a,b (IC50: 60.27 and 93.5 nM) and 23 (IC50: 147 nM) were also potent EGFR inhibitors, which were comparable to sorafenib (IC50: 55.43 nM). Mechanistically, hybrid 22a arrested the cell cycle on MCF-7 cells at G1/S phase and induced apoptosis.

4. Quinazoline-indole/pyrrole/furan hybrids

Quinazoline-indole hybrid 24a (Figure 4; IC50: 0.9 and 0.9 nM, MTT assay) and its 7-azaindole derivative 24b (IC50: 2.1 and 2.1 nM) exhibited pronounced antiproliferative activity against MCF-7 and doxorubicin-resistant MCF-7/Adr breast cancer cell lines, which was higher than that of combretastatin A-4 (CA-4, IC50: 4.8 and 3.1 nM) [44]. Mechanistic studies revealed that hybrid 24a could induce apoptosis in breast cancer cells by arresting cell cycle at G2/M phase, depolarizing mitochondria and inducing intracellular ROS. In addition, hybrid 24a inhibited tubulin polymerization and aryl hydrocarbon receptor (AhR) expression. In the MCF-7 ×enografted mice model, hybrid 24a (1.0 mg/kg, intravenous injection) achieved significant tumor growth inhibition with a TGI value of 81.1% without evident influence on body weight, while paclitaxel (TGI: 84.2%) showed the similar in vivo efficacy at 10-fold dose (10 mg/kg, intravenous injection). Collectively, hybrid 24a as a potent preclinical candidate for breast cancer therapy was worthy of further evaluations.

Figure 4.

Figure 4.

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Structures of quinazoline-indole hybrids 24–34.

Quinazoline-indole hybrid 25 (IC50: 0.25 nM, CellTiter Glo assay) was  ~  8.0 times more potent than isoCA-4 (IC50: 1.98 nM) against MDA-MB-231 breast cancer cells and had the potential to overcome drug resistance as evidenced by that hybrid 25 (IC50: 0.10 nM vs 0.26 nM) was more sensitive to doxorubicin-resistant K562R cancer cells over drug-sensitive K562 cells [45]. Mechanistically, hybrid 25 blocked cell cycle in the G2/M phase and induced mitochondrial dysfunction. Moreover, hybrid 25 (t1/2: 140 and 145 h) also possessed better metabolic stability than isoCA-4 (t1/2: 18 and 30 h) in rat and human liver microsomes.

Quinazoline-indole hybrids 26 (IC50: 0.35–7.32 µM, MTT assay) exhibited promising antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines, and the SAR implied that dimethoxy or ethoxy on the phenyl ring boosted up the activity [46]. Particularly, hybrids 26a (IC50: 350 and 447 nM) and 26b (IC50: 715 and 921 nM) were not inferior to erlotinib (IC50: 3.57 and 0.55 µM) against the tested breast cancer cell lines. Mechanistically, hybrid 26a could arrest cell cycle at the G2/M phase and induce apoptosis.

FQ393 (27, IC50: 4.90 and 10.80 µM, MTT assay), a quinazoline-indole hybrid, showed considerable antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines and was able to induce apoptosis [47]. SKLB-197 (28, IC50: 1.97 µM, MTT assay), a pyrazole-containing quinazoline-indole hybrid, was a potent Rad3-related (ATR) kinase inhibitor (IC50: 13 nM) and exhibited considerable antiproliferative activity against MCF-7 breast cancer cells [48]. After oral administration, SKLB-194 (10 mg/kg) demonstrated desirable pharmacokinetic properties with t1/2 of 1.14 h, Cmax of 895.28 ng/mL, AUC0-∞ of 2719.61 ng•h/mL, and bioavailability of 43.1%, and no significant changes in body weight and no obvious damage in the vital organs (heart, liver, spleen, lung, and kidney) were observed in mice model.

Quinazolinone-indole hybrids 29a,b (IC50: 0.28 and 2.7 µM, MTT assay) were active against MCF-7 breast cancer cells [49], and the SAR illustrated that incorporation of phenyl ring into N-1 position of indole moiety was tolerated, and hybrid 30 (IC50: 570 nM, MTT assay) showed excellent antiproliferative activity against MCF-7 cancer cells [50]. Quinazolinone-oxindole hybrid 31 (IC50: 29.75 nM) not only was superior to erlotinib (IC50: 60.92 nM) in terms of inhibition of EGFR but also demonstrated higher antiproliferative activity than erlotinib (IC50: 8.76 µM vs 9.67 µM) against MCF-7 cancer cells [51].

Quinazolinone-oxindole hybrid 32 (GI50: 1.21–4.99 µM, SRB assay) showed promising antiproliferative activity against MCF-7, MDA-MB-231, HS 578T, BT-549, T-47D and MDA-MB-468 breast cancer cell lines [52], whereas hybrids 33a,b (IC50: 890 and 890 nM, MTT assay) were more potent than gefitinib (IC50: 16.71 µM) and alpelisib (IC50: 1.89 µM) against MCF-7 breast cancer cells [53]. The SARs elucidated that (1) phenyl ring at C-3 position of oxindole moiety increased the activity; (2) incorporation of indole moiety into C-3 position of oxindole motif could improve the activity to some extent, and hybrids 34a,b (IC50: 440 and 690 nM, MTT assay) showed enhanced activity [53]. Moreover, hybrid 32 (IC50: 470 nM) was a potent VEGFR-2 inhibitor and stalled the cell cycle at the G2/M phase and promoted its necrosis, whereas hybrid 33b (IC50: 9.11 nM) displayed excellent inhibitory effects toward EGFR and could potentially inhibit the PI3K pathway, induce the production of ROS in cellular mitochondria and disrupt the mitochondrial membrane potential, thus mediating mitochondrial dysfunction and promoting apoptosis.

Indolo[2,1-b]quinazoline-6,12-dione 35 (Figure 5; IC50: 1.78 µM, MTT assay) was 25.4 folds more potent than gefitinib (IC50: 45.31 µM) against MDA-MB-231 breast cancer cells and could arrest G2/S cell cycle as well as induce apoptosis [54]. CIQ (36, IC50: 710 and 490 nM, MTT assay) was superior to tryptanthrin (IC50: 2.87 and > 10 μM) against MCF-7 and MDA-MB-231 breast cancer cell lines [55]. Moreover, CIQ could induce caspase-dependent apoptosis, ROS generation, mitogen-activated protein kinase (MAPK) signaling modulation, and invasion inhibition. Hybrids 37a-c (IC50: 3.87–4.92 µM, MTT assay) were not inferior to erlotinib (IC50: 3.50 and 3.13 µM) against MCF-7 and MDA-MB-231 breast cancer cell lines, and the SAR indicated that halogen atoms at both R1 and R2 positions were beneficial for the activity [56]. The most active hybrid 37a (IC50: 190 nM) also demonstrated excellent inhibitory activity against EGFR, but the activity was slightly lower than that of erlotinib (IC50: 80 nM). 5,11-Dioxoisoindolo[2,1-a]quinazoline BBAP-8 (38, IC50: 16.59 µM, MTT assay) was more active than tamoxifen (IC50: 20.95 µM) against MCF-7 breast cancer cells and had the potential to activate hypoxia-inducible factor-1 (FIH-1) with the downregulation of glucose transporter-1 (GLUT-1), VEGF, and Twist-1 [57]. Moreover, BBAP-8 fostered apoptosis, when evaluated through Bcl-2, BAX, caspase-8, and caspase-3.

Figure 5.

Figure 5.

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Structures of quinazoline-indole/pyrrole/furan hybrids 35–46.

Spiro[indolo[2,1-b]quinazoline-pyrano[2,3-c]pyrazole] derivatives 39 (IC50: 10.89–92.79 µM, MTT assay) showed moderate antiproliferative activity against MDA-MB-231 breast cancer cells, and the SAR suggested that halogen atom at R position was favorable to the activity [58–60]. Amongst them, hybrids 39a,b (IC50: 12.83 and 10.89 µM, MTT assay) were more active than etoposide (IC50: 30.63 µM) against MDA-MB-231 breast cancer cells and were nontoxic (IC50: >100 µM) toward normal HDF cells [60].

Erlotinib-heptamethine cyanine dye hybrids 40 (IC50: <125–833 nM, MTT assay) were highly active against MDA-MB-231 breast cancer cells, and the SAR illustrated that butyl group at N-1 position of indole moiety was critical for the high activity [61]. In particular, hybrids 40a-d (IC50: <125 nM) were > 124 times superior to erlotinib (IC50: 15.51 µM) against MDA-MB-231 breast cancer cells, and hybrid 40a (IC50: 33.2 µM) displayed low cytotoxicity toward normal MCF-10A breast cells. Quinazoline-pyrido[3,4-b]indole hybrid 41 (IC50: 43.98 µM, MTS assay) isolated from the roots of Peganum harmala L. was active against MDA-MB-231 breast cancer cells, but the activity was lower than that of etoposide (IC50:3.90 µM) [62]. The SAR indicated that methyl group at C-2 position of quinazoline moiety was favorable to the activity, while quinazoline moiety was not critical for the activity, and replacement by pyrimidine resulted in improved activity.

Quinazoline-pyrrole hybrid 42 (IC50: 5.22, 32.54 and 12.30 µM, MTT assay) was not inferior to erlotinib (IC50: 16.10, 23.81 and 51.65 µM) against MDA-MB-468, MCF-7 and SK-BR-3 breast cancer cell lines and was nontoxic (IC50: >100 µM) toward normal HEK 293T cells [63]. The SAR demonstrated that fluoro on the phenyl ring was favorable to the activity, and movement of pyrrole fragment from C-6 position of quinazoline moiety to C-4 position was permitted as evidenced by that hybrids 43a,b (IC50: 43.99 and 47.70 µM, MTT assay) were superior to doxorubicin (IC50: 54.29 µM) against MCF-7 breast cancer cells [63,64].

Quinazoline-furan hybrids 44 (IC50: 0.78–9.79 µM, CCK-8 assay) and their regio-isomers 45 (IC50: 1.00–10.65 µM, MTT assay) exhibited promising antiproliferative activity against MCF-7 and SK-BR-3 breast cancer cell lines [65]. The SARs elucidated that (1) electron-withdrawing group on the phenyl ring increased the activity [65]; (2) movement of furan moiety from C-6 position of quinazoline moiety to C-2 position led to loss of activity, and hybrid 46 (IC50: 16.7 µM, MTT assay) showed lower activity than doxorubicin (IC50: 4.67 µM) against MCF-7 breast cancer cells [66,67]. In particular, hybrids 44a-f (IC50: 0.78–1.83 µM) and 45a-f (IC50: 1.00–1.73 µM) were not inferior to lapatinib (IC50: 1.12 and 3.74 µM) against MCF-7 and SK-BR-3 breast cancer cell lines. Further studies revealed that hybrid 44a could inhibit the phosphorylation of EGFR and HER-2, arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. In the SK-BR-3 ×enografted mice model, hybrid 44a (TGI: 68.98% at 30 mg/kg via intragastric administration) showed obvious tumor growth inhibition, and no significant loss of body weight was observed. Collectively, hybrid 44a was a promising therapeutic candidate for breast cancer therapy and deserved further evaluations.

5. Quinazoline-chalcone hybrids

The antiproliferative SARs of quinazolinone-chalcone hybrids 47 (Figure 6; IC50: 1.1–10.9 µM, MTT assay) against MCF-7 breast cancer cells illustrated that allyl at N-3 position of quinazolinone moiety was indispensable for the high activity [68,69]. Amongst them, hybrids 47a-e (IC50: 1.1–2.8 µM) were found to be most active against MCF-7 breast cancer cells and were nontoxic (IC50: >50 µM) toward normal MCF-10A breast cells. In particular, hybrid 47a was a dual inhibitor of EGFR (IC50: 110 nM) and BRAF (IC50: 650 nM) and was not inferior to doxorubicin (IC50: 1.1 µM vs 0.9 µM) against MCF-7 breast cancer cells. Further studies indicated that hybrid 47a could increase caspase-8 and 9, induce Bax and cytochrome c, decrease Bcl-2 protein levels, and arrest cell cycle at the pre-G1 and G2/M phases.

Figure 6.

Figure 6.

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Structures of quinazoline-chalcone hybrids 47–52.

Quinazolinone-chalcone hybrids 48 (IC50: 4.6–19.1 µM, MTT assay) showed considerable antiproliferative activity against MDA-MB-231 breast cancer cells, and the SARs indicated that (1) fluoro on the phenyl ring was favorable to the activity; (2) introduction of electron-withdrawing group into R position enhanced the activity [70,71]. Among them, hybrids 48a-c (IC50: 4.6, 5.0 and 5.9 µM) were found to be most potent against MDA-MB-231 breast cancer cells, but the activity was lower than that of doxorubicin (IC50: 0.16 µM). Mechanistic studies indicated that hybrid 48a could arrest cell cycle at S- or G2/M-phase and induce apoptosis through induction of caspase-3 and PARP-1 cleavage.

Quinazolinone-chalcone hybrid 49 (GI50: 1.81–9.17 µM, SRB assay) displayed considerable antiproliferative activity against MDA-MB-231, MCF-7, HS 578T, BT-549, T-47D and MDA-MB-468 breast cancer cell lines, but the activity was inferior to that of doxorubicin (IC50: 0.027–0.512 µM) [72]. The SAR demonstrated that introduction of substituent into chalcone moiety reduced the activity. Further studies showed that hybrid 49 could interact with DNA through intercalation and groove binding.

5,6-Dihydro-[((1,2,4))]triazolo[4,3-c]quinazoline-chalcone hybrid 50 (IC50: 7.88 µM, MTT assay) showed promising antiproliferative activity against MCF-7 breast cancer cells, and the SAR demonstrated that introduction of phenyl ring into C-2 position of quinazoline moiety was beneficial for the activity as evidenced by that hybrids 51a,b (IC50: 4.81 and 3.40 µM, MTT assay) were superior to doxorubicin (IC50: 4.86 µM) against MCF-7 breast cancer cells [73]. Besides, hybrids 51a,b (IC50: 27.81 and 18.80 µM) displayed relative low cytotoxicity toward normal WI38 cells. Moreover, hybrids 51a,b (IC50: 147 and 329 nM) were potent EGFR inhibitors and could induce apoptosis as well as arrest cell cycle at S phase.

1,3,5-Triazine- and 1,2,3-triazole-containing quinazoline-chalcone hybrids 52 (IC50: 0.09–9.42 µM, MTT assay) exhibited prominent antiproliferative activity against MCF-7 breast cancer cells, and the SAR revealed that incorporation of electron-withdrawing group into phenyl ring boosted up the activity [74]. In particular, hybrids 52a,b (IC50: 90 and 130 nM) were 23.4 and 16.2 times more potent than etoposide (IC50: 2.11 µM) against MCF-7 breast cancer cells.

6. Quinazoline-hydroxamic acid hybrids

The antiproliferative SARs of quinazoline-hydroxamic acid hybrids 53 (Figure 7, IC50: 1.32–22.42 µM, MTT assay) against MDA-MB-231 breast cancer cells elucidated that extension of the carbon spacer between hydroxamic acid and phenyl ring was beneficial for the activity [75]. Among them, hybrids 53a-c (IC50: 1.32, 2.37 and 3.40 µM) were not only superior to vorinostat (IC50: 8.14 µM) against MDA-MB-231 breast cancer cells but also showed great inhibitory effects (IC50: 11.68, 55.3 and 110 nM) against HDAC6. Further studies showed that hybrids 53a,b could increase the acetylation level of intracellular proteins, especially in α-tubulin and heat shock protein 90 (HSP90), induce apoptosis, autophagy and migration inhibition. Moreover, hybrid 53a (20 mg/kg, oral administration) exhibited desirable pharmacokinetic properties in beagle dogs: t1/2 was 1.24 h, tmax was 0.79 h, Cmax was 120.36 ng/mL, and AUC0-∞ was 1289.4 h•ng/mL. In the MDA-MB-231 ×enografted zebrafish model, hybrid 53a (2.5 µg/mL) exhibited higher antiproliferation (55% vs 45%) and antimigration (45% vs 25%) activity than vorinostat with a dose-dependent manner. Collectively, hybrid 53a as a novel oral HDAC inhibitor with a potential capacity for breast cancer therapy deserved further evaluations.

Figure 7.

Figure 7.

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Structures of quinazoline-hydroxamic acid hybrids 53–61.

Quinazoline-hydroxamic acid hybrid 54 (IC50: 0.80 and 0.55 nM, CellTiter Glo assay) exhibited pronounced antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines, which was higher than that of isoCA-4 (IC50: 8.0 and 4.0 nM) [76]. Hybrid 54 (IC50: 280 nM) was a potent HDAC8 inhibitor and had the potential to overcome multidrug resistance as evidenced by that hybrid 54 (IC50: 1.63 nM) demonstrated excellent antiproliferative activity against multidrug-resistant K562R cancer cells. Mechanistically, hybrid 54 induced cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Moreover, hybrid 54 also possessed excellent stability in human (t1/2: 9.0 h, CLint: 1.28 mL/min/kg) and rat (t1/2: 3.53 h, CLint: 3.27 mL/min/kg) liver microsomes, revealing its potential as novel antibreast cancer candidate.

Quinazoline-hydroxamic acid hybrids 55 (IC50: 0.26–4.32 µM) showed potent antiproliferative activity against MCF-7 breast cancer cells, and the SAR indicated that introduction of either electron-donating or electron-withdrawing group into phenyl ring at C-2 position of quinazoline moiety decreased the activity [77]. Amongst them, hybrids 55a-c (IC50: 260, 570 and 780 nM) which were superior to vorinostat (IC50: 2.49 µM) and doxorubicin (IC50: 2.16 µM) against MCF-7 breast cancer cells also exhibited great inhibitory effects (IC50: 210, 110 and 160 nM) against HDACi. Furthermore, hybrids 55a-c (the concentration causing 50% of maximum haemolysis/HD50: 51.09, 95.12 and 83.71 µg/mL) displayed low cytotoxicity to human erythrocytes, indicating the lack of hemolytic toxicity.

Quinazoline-hydroxamic acid hybrids 56a (IC50: 9.2, 3.2 and 17 nM) and 56b (IC50: 1.3, 89 and 13 nM) were potent multitargeted inhibitors of glucagon-like peptide (GLP) and HDAC1/6 and showed considerable antiproliferative activity (IC50: 7.89 and 9.30 µM, MTT assay) against MDA-MB-231 breast cancer cells, which was comparable to that of vorinostat (IC50: 2.36 µM) [78]. Besides, hybrid 56b could inhibit the methylation and deacetylation of H3K9 on protein level and induce cancer cell apoptosis, G0/G1 cell cycle arrest, and partly block migration and invasion. Moreover, hybrid 56b also possessed considerable metabolic stability in rat liver microsomes human with t1/2 of 16.25 min and CLint of 152.86 mL/min/kg.

Quinazolinone-hydroxamic acid hybrids 57 (IC50: 3.44–36.9 µM, MTT assay) showed considerable antiproliferative activity against MCF-7 breast cancer cells, and the SAR proved that fluoro at para-position of benzyl group was critical for the high activity [79]. The representative hybrid 57a (IC50: 3.44 µM) was comparable to belinostat (IC50: 2.60 µM) against MCF-7 cancer cells and demonstrated profound inhibitory effects (IC50: 0.3 and 0.8 nM) against HDAC6 and HDAC8.

Pyrimidine-containing quinazolinone-hydroxamic acid hybrids 58 (GI50: 1.8, 0.4 and 0.3 µM, SRB assay) and 59 (GI50: 1.8, 2.0 and 1.2 µM) were more active than idelalisib (GI50: 42.3, 6.0 and 5.2 µM) and vorinostat (GI50: 2.5, 3.6 and 0.5 µM) against MDA-MB-231, HS 578T and T-47D breast cancer cell lines [80]. In addition, hybrids 58 (IC50: 2.0, 0.2 and 28 nM) and 59 (IC50: 9.0, 7.0 and 120 nM) were highly active against PI3Kγ/δ and HDAC6. Moreover, hybrid 59 (50 mg/kg, intraperitoneal injection) also possessed promising liver microsomal (t1/2: 32.2, 74.4 and 98.6 min) and cytosol (t1/2: 105.5, >120 and >120 min) stability in human, mouse and rat and considerable pharmacokinetic properties with t1/2 of 2.7 h, Cmax of 7783 ng/mL, and AUC0-∞ of 8493 ng•h/mL.

Benzofuran-containing quinazoline-hydroxamic acid hybrid 60 (IC50: 17.86 µM, MTT assay) was not inferior to vorinostat (IC50: 11.82 µM) and fruquintinib (IC50: >20 µM) against MCF-7 breast cancer cells and was highly active against VEGFR-2 and HDAC1 with IC50 values of 57.83 and 9.82 nM [81]. Mechanistic studies revealed that hybrid 60 blocked the cell cycle at the S and G2 phases, induced apoptosis, and had significant anti-angiogenic effect.

Phthalazino[1,2-b]quinazolinone-hydroxamic acid hybrids 61 (IC50: 0.0706–1.27 µM, MTT assay) exhibited prominent antiproliferative activity against MCF-7 breast cancer cells, and the SARs illustrated that (1) extension of the carbon spacer between phthalazino[1,2-b]quinazolinone and hydroxamic acid enhanced the activity; (2) methyl or halogen atoms at C-6 position of quinazolinone moiety was favorable to the activity [82]. Particularly, hybrids 61a-d (IC50: 70.6–92.9 nM) were superior to vorinostat (IC50: 1.11 µM) in terms of inhibition of MCF-7 cancer cells and displayed great inhibitory effects (IC50: 8.17–61.7 nM) against HDAC1/2/3. Mechanistically, these hybrids could suppress cancer cell proliferation through promoting the acetylation of histone 3 (H3) and α-tubulin, and activating the p53 signal pathway.

7. Quinazoline-hydrazone hybrids

Quinazoline-hydrazone hybrid 62 (Figure 8, GI50: 1.79–3.28 µM, SRB assay) exhibited excellent antiproliferative activity against MCF-7, MDA-MB-231, MDA-MB-468, HS 578T, BT-549 and T-47D breast cancer cell lines and was comparable to erlotinib (IC50: 69 nM vs 45 nM) in terms of inhibition of EGFR [83]. The SAR demonstrated that thioether linker enhanced the activity to some extent, and hybrid 63 (GI50: 2.68–8.19 µM, SRB assay) without thioether linker showed reduced activity against the tested breast cancer cell lines [84]. Mechanistically, hybrid 62 induced apoptosis and caused induction of cell cycle arrest in HS 578 T cells at the G1/S phase, whereas hybrid 63 arrested the cell cycle progression in MDA-MB-231 cells at the G2/M phase and induced apoptosis.

Figure 8.

Figure 8.

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Structures of quinazoline-hydrazone hybrids 62–69.

Quinazoline-hydrazone hybrids 64 (IC50: 3.91–40.86 µM, MTT assay) were active against MCF-7 breast cancer cells, and the SARs implied that (1) methyl on the phenyl ring at N-3 position of quinazolinone moiety was not critical for the activity, and hybrids 65a,b (IC50: 6.77 and 8.86 µM, MTT assay) also demonstrated excellent activity [85,86]; (2) removal of phenyl ring between quinazoline and hydrazone did not influence the activity obviously as evidenced by that hybrids 66 (IC50: 30.85–52.49 µM, MTT assay) also showed moderate antiproliferative activity against MCF-7 cancer cells [87]; (3) the terminal phenyl ring was not essential for the activity, and hybrid 67 (IC50: 13.79 µM, MTT assay) demonstrated considerable antiproliferative activity against MCF-7 cancer cells [88]. The representative hybrid 64a (IC50: 3.91 µM) was  ~  2 folds more potent than doxorubicin (IC50: 7.67 µM) and sorafenib (IC50: 7.21 µM) against MCF-7 cancer cells. Moreover, hybrid 64a (IC50: 290 nM) was an excellent VEGFR-2 inhibitor, which was superior to sorafenib (IC50: 588 nM).

Quinazoline-2,4(1H,3H)-dione-hydrazone hybrids 68 (IC50: 5.27–7.44 µM, MTT assay) exhibited prominent antiproliferative activity against MCF-7 breast cancer cells, and the SAR illustrated that introduction of iodo into C-7 position of quinazoline-2,4(1H,3H)-dione moiety was tolerated, and hybrids 69 (IC50: 7.15–9.15 µM, MTT assay) also showed promising activity against MCF-7 cancer cells [89,90]. The representative hybrids 68a-c (IC50: 5.67, 5.27 and 5.80 µM) not only were more potent than doxorubicin (IC50: 6.75 µM) and sorafenib (IC50: 7.26 µM) against MCF-7 breast cancer cells but also (IC50: 120, 120 and 130 nM) were comparable to sorafenib (IC50: 100 nM) in inhibition of VEGFR-2, whereas hybrids 69a,b were potent dual VEGFR-2 (IC50: 1.0 and 0.9 µM) and EGFRT790M inhibitors, demonstrating their potential as novel anti-breast cancer candidates.

8. Conclusions

Breast cancer is a pervasive and multifaceted disease, resulting in substantial morbidity and mortality worldwide. Chemotherapeutics are critical for the treatment of breast cancer, but multidrug resistance is a major obstacle for effective therapy, creating an urgent need to develop novel antibreast cancer chemotherapeutics. Quinazoline hybrids have already been applied for the exploitation of innovative chemotherapeutics to combat this disease since they have potential advantages in improve anticancer therapeutic efficacy, reduce adverse effects and circumvent drug resistance. Moreover, quinazoline-furan-sulfone hybrid lapatinib has already been approved for breast cancer therapy, demonstrating that quinazoline hybrids are fertile sources for the development of novel chemotherapeutics for clinical deployment in the control and eradication of breast cancer.

This review emphasizes the current landscape of quinazoline hybrids including quinazoline-sulfone/sulfonate/sulfonamide hybrids, quinazoline-(thio)urea hybrids, quinazoline-indole/pyrrole/furan hybrids, quinazoline-chalcone hybrids, quinazoline-hydroxamic acid hybrids and quinazoline-hydrazone hybrids with antibreast cancer potential, developed from 2020 onwards. Conclusively, sulfone, sulfonate, sulfonamide, (thio)urea, indole, pyrrole, furan, chalcone, hydroxamic acid and hydrazone are useful antibreast cancer pharmacophores, and rational hybridization of these pharmacophores with quinazoline has the potential to provide novel antibreast cancer candidates with excellent in vitro and/or in vivo therapeutic potential against both drug-sensitive breast cancers and their multidrug-resistant forms.

Funding Statement

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Fujian Talent Funds (Fujian Provincial Hospital) [NO. 00802741,00801109]; the Natural Science Foundation of Fujian Province of China [NO.2021J01379]; Young and Middle-aged Talents Training Project of Fujian Provincial Health Commission [NO. 2021GGA001]; Joint Funds for the Innovation of Science and Technology of Fujian Province, China [NO.2024Y9018, 2023Y9302]; Department of Finance, Fujian Province [NO. (2024)881–2024058].

Article Highlights

  1. Quinazoline hybrids could act on diverse biological targets in breast cancer cells;

  2. Quinazoline hybrids possessed excellent in vitro and in vivo activity against both drug-sensitive and drug-resistant breast cancers;

  3. Several quinazoline hybrids are already being applied in clinics or under clinical evaluation for the treatment of breast cancer.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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