Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation

Abstract

The mitogen-activated protein kinase (MAPK) pathway—also known as the RAS/RAF/MEK/ERK pathway—is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the early 1980s, the pathway’s extracellular signal-regulated kinase (ERK) subfamily was identified in the 1990s. The ERK family includes several isoforms—ERK1, ERK2, ERK3, ERK5, and ERK6—with ERK1 (MAPK3) and ERK2 (MAPK1) being the most well-characterised and playing central roles in MAPK signalling. Deregulation of ERK signalling (commonly referred to as the ERK pathway or ERKp) has been implicated in approximately 40% of human cancers. This review focuses on the structural insights of ERK1/2 and their critical role in the MAPK signalling cascade. Despite their clinical significance, no ERK inhibitors have yet been approved by the FDA. Several molecules—such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204—are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.

Graphical Abstract

Introduction

Cancer is characterised by the uncontrolled proliferation of cells, which can invade surrounding tissues and spread to distant parts of the body. Under normal physiological conditions, human cells divide to produce new cells as needed for growth, repair, and maintenance. This tightly regulated process ensures tissue homeostasis. Damaged, aged, or unnecessary cells typically undergo apoptosis, a form of programmed cell death, and are replaced by healthy new cells. However, in cancer, this balance is disrupted—cells continue to divide uncontrollably, and the normal mechanisms of apoptosis may be evaded, leading to tumour formation and progression¹.

The mitogen-activated protein kinase (MAPK) pathway—also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in cell growth, proliferation, and survival. Mutations in its key components, including RAS, RAF, MEK, and ERK, have been frequently observed in various cancers and contribute significantly to tumour development and progression^2–5. MAPK signals are transmitted through extracellular signal-regulated kinases (ERKs), a group of serine/threonine protein kinases that function as key signal transduction molecules that regulates growth factors, hormones, neurotransmitters, and other extracellular stimuli transmit signals⁶. The MAPK pathway was first discovered in the early 1980s, with the ERK subfamily being identified in the 1990s. A wide range of extracellular stimuli and intracellular processes can activate the ERK cascade, as illustrated in Figure 1. The ERK family includes several isoforms—ERK1, ERK2, ERK3, ERK5, and ERK6. Among these, ERK1 (MAPK3) and ERK2 (MAPK1) most well-characterised and playing essential roles in the MAPK/ERK signalling pathway as closely related kinases with key roles in cellular signalling. These two kinases are crucial for regulating cellular processes such as proliferation, differentiation, and survival. Between 1993 and 1995, aberrant activation of ERK was linked to mutations in upstream components such as RAS and RAF genes—particularly BRAF (v-Raf murine sarcoma viral oncogene homolog B1)—which led to uncontrolled cellular proliferation^3,7,8.

Figure 1.

Regulation of ERK1/2 in MAPK signalling cascade.

In ERK family, the ERK1/2 cascade is the first and most well-characterised mitogen-activated protein kinase (MAPK) pathway. Operating downstream of Ras, it typically functions through the sequential phosphorylation and activation of MAP3Ks⁵. Based on the components of the MAPK module, four major MAPK cascades have been identified: ERK1/2, p38 MAPK, c-Jun N-terminal kinase (JNK), and ERK5⁹. These cascades are activated by upstream MAPK kinases (MAP2Ks), with activation segments containing the conserved Thr-Xaa-Tyr motif, essential for dual phosphorylation and full activation¹⁰. In addition to these conventional MAPKs, atypical MAPKs such as Nemo-like kinase (NLK), ERK3, ERK4, and ERK8 have also been identified, although they differ in regulation and function¹¹.

The structural characteristics and biological roles of conventional MAPKs have been extensively studied. Because the MAPK/ERK pathway regulates a wide array of essential cellular processes-including proliferation, differentiation, apoptosis, and stress response—it is tightly controlled by various regulatory mechanisms. These include scaffold proteins, phosphatases (with alternatively spliced isoforms), and subcellular localisation^12,13. Dysfunction in the ERK cascade can have serious consequences for both cellular and organismal health. Over activation of components in this pathway, particularly through mutations or aberrant signalling has been implicated in numerous cancer diseases. MEK1/2, the upstream kinases, directly activates ERK1/2, which lie at the terminal end of the pathway. Once activated, ERK1/2 phosphorylate a range of nuclear and cytoplasmic substrates—including transcription factors and regulatory molecules—leading to the rapid induction of early response genes that control cell proliferation^14–16. Ultimately, these activated proteins promote the expression of additional downstream effectors, triggering and regulating oncogenic transformation or uncontrolled cell proliferation. Due to its central position in the pathway, inhibiting ERK1/2 activity presents a promising strategy to prevent the pathological outcomes caused by excessive upstream signalling and over activation of ERK1/2¹⁷.

Deregulation of ERK signalling (often referred to as ERK pathway or ERKp) has since been associated with approximately 40% of human cancers. This pathological activation results from genetic alterations affecting the core effectors or regulatory elements within the ERK pathway¹⁸. Given its frequent up regulation in malignancies, the ERK cascade represents a critical target for the development of novel anticancer therapies¹⁹.

Structural insight of ERK1/2

The ERK protein family mainly two isoforms ERK1 (41 kDa) and ERK2 (43 kDa) exhibit a high degree of sequence homology, sharing approximately 84% sequence identity, and are often referred to collectively as ERK1/2 due to their overlapping and functionally similar roles. Despite their similarities, subtle structural distinctions contribute to differences in signalling specificity. Notably, both ERK1 and ERK2 possess unique N-terminal and C-terminal extensions that aid in their regulatory and substrate recognition functions. ERK1 includes a 17-amino acid insertion in its N-terminal region, distinguishing it from ERK2. Additionally, both isoforms share a common 31-amino acid insertion within their kinase domain, which is a defining feature of the ERK family. ERK1 is composed of 379 amino acids, whereas ERK2 consists of 360 amino acids. Detailed structural insights into ERK1/2 are presented in Figure 2 and Table 1. Figure 3 and Tables 2 and 3 illustrate the identified pocket numbers of ERK1 and ERK2 proteins, along with their respective surface areas (Ų), volumes (ų), and druggability scores^20,21.

Figure 2.

 Structural insight of ERK1/2 protein.

Table 1.

Structural components and number of residues in ERK1 & ERK2.

Structural insight	Residues in ERK1	Residues in ERK2
-	Human ERK1 consists of 379 amino acid residues	Human ERK2 consists of 360 amino acid residues
-	Isoleucine is present	Leucine is present
-	Mice’s development does not require the erk1 gene.	Embryonic lethality results from erk2 gene ablation.
Protein kinase domain	42–330	25–313
Glycine-rich loop	49–54	32–37
The K of K/D/D, or the β3-lysine	71	54
αC-glutamate	88	71
Hinge residues	123–26	106–109
Gatekeeper residue	Gln122	Gln105
Catalytic HRD	164–166	147–149
Catalytic loop lysine	168	151
DFG of the activation segment	184–186	167–169
Activation lip phosphorylation sites	T202, Y204	T185, Y187
APE end of the activation segment	212–214	195–197
No. of residues	379	360
Molecular weight (kDa)	43.1	41.4
UniProtKB ID	P27361	P28482

Figure 3.

Structural insight of ERK1/2 protein with different pocket number.

Table 2.

ERK1/2 protein pocket with amino acid sequences.

Pocket no.	ERK1 protein (PDB ID:4QTB)	ERK2 protein (PDB ID:5NHJ)
P0	GLN34, PHE36, ILE48, ALA52, TYR53, GLY54, MET55, VAL56, ALA69, ILE70, LYS71, LYS72, ILE73, SER74, PRO75, TYR81, ARG84, THR85, GLU88, ILE89, ILE101, ILE120, VAL121, GLN122, ASP123, LEU124, MET125, GLU126, THR127, ASP128, LYS131, HIS164, ARG165, ASP166, SER170, ASN171, LEU173, ILE174, CYS183, ASP184, PHE185, GLY186, LEU187, ALA18	ILE31, GLY32, GLU33, GLY34, ALA35, TYR36, GLY37, MET38, VAL39, ALA52, ILE53, LYS54, LYS55, ILE56, ARG67, THR68, GLU71, ILE72, LEU75, ILE84, ILE86, ILE89, ILE103, GLN105, ASP106, LEU107, MET108, GLU109, THR110, ASP111, LYS114, ASP149, SER153, ASN154, LEU156, CYS166, ASP167, PHE168, GLY169
P1	THR80, CYS82, GLN83, ARG84, LEU86, ARG87, GLN90, HIS164, ARG165, ASP166, LEU167, LYS168, PHE185, GLY186, LEU187, ALA188, ARG189, ILE190, ALA191, ASP192, THR198, GLY199, THR202, GLU203, TYR204, VAL205, ALA206, THR207, TYR210, ARG211, ALA212, ILE215, MET216, SER219, LYS220, GLY221, TYR222, ILE226, ASP227, TRP229, SER230, TYR250, THR347, PHE348, ALA349, MET350, LEU352, ASP353, LEU360	LEU146, PRO176, ASP179, HIS180, ALA195, PRO196, GLU197, ILE198, LEU200, ASN201, SER202, GLY204, TYR205, THR206, SER208, ILE209, ASP251, CYS254, ILE255, PHE296, ASN297, PRO298, HIS299, ARG301
P2	GLN137, LEU138, SER139, ASN140, ILE143, ALA236, GLU237, LEU239, SER240, ARG242, PRO243, ILE244, ILE260, LEU295, PHE296, PRO297, LYS298, SER299, ASP300	THR63, GLN66, ARG67, ARG70, GLU71, ARG148, PHE168, GLY169, LEU170, ALA171, ARG172, THR181, GLY182, LEU184, THR185, GLU186, TYR187, VAL188, GLU197, ILE198, MET199, LEU200, ASN201, SER202, LYS203, TYR205
P3	ASP37, VAL38, GLY39, ARG41, TYR42, ASP105, ILE106, LEU107, ARG108, ALA109, ALA114, MET115, ARG116, ASP117, TYR119, THR368, PHE371, GLN372, PRO373, GLY374	LEU69, ARG70, LYS73, ILE74, LEU76, ARG77, VAL145, ALA171, ARG172, VAL173, PHE329, PHE331, ASP332, MET333, LEU335, GLU350
P4	ASN255, LEU258, GLY259, GLY262, SER263, PRO264, LEU269, LEU281, GLN282, LEU284, PRO285, SER286, LYS287	LEU237, ASN238, LEU241, GLY242, GLY245, SER246, PRO247, LEU252, LEU264, LEU265, LEU267, PRO268, HIS269, LYS270
P5	ASP196, ALA212, PRO213, GLU214, ILE215, LEU217, ASN218, SER219, GLY221, TYR222, THR223, LYS224, SER225, ILE226, ASP268, CYS271, ILE272, PHE313, ASN314, PRO315, ASN316, ARG318	LYS138, HIS141, SER142, THR206, LYS207, SER208, ILE211, PRO298, ARG301, ILE302, GLU303, VAL304, GLU305, ILE324
P6	LEU261, GLY262, SER263, PRO264, SER265, ASP268, LYS289, ASP308, LEU311, THR312, PHE313, ASN314, LYS317	LEU112, TYR113, LEU116, LYS117, LYS151, PRO152, SER153, THR190, TRP192, TYR193, GLU220, ASN224, ARG225, PRO226
P7	LEU129, TYR130, LEU133, LYS134, LYS168, PRO169, SER170, THR207, TRP209, TYR210, GLU237, ASN241, ARG242, PRO243	HIS120, LEU121, SER122, ASN123, ILE126, MET221, LEU222, SER223, PHE279, PRO280, ASN281, ALA282, ASP283, ALA286, TYR312
P8	PRO25, GLY26, GLU27, VAL28, GLU29, PHE36, ASP37, VAL38, GLY39, PRO40, TYR42, THR43, GLN44, LEU45	ILE240, LEU241, LEU244, GLY245, SER246, PRO247, SER248, ASP251, LYS272, TRP275, LEU290, ASP291, LEU294, THR295, PHE296
P9	GLU126, THR127, LEU132, GLN136, LEU138, HIS142, PHE146, ILE174, ASN175, THR176, CYS178	GLU109, THR110, LEU115, GLN119, HIS120, LEU121, SER122, HIS125, PHE129, LEU157, ASN158, THR159, THR160, CYS161
P10	GLU98, ASN99, TYR145, TYR148, GLN149, ARG152, ASP179, LEU180, LYS181, TYR333, ASP338	HIS147, ARG148, ASP149, LEU150, LYS151, TYR187, ALA189, THR190, TYR193, ARG194, ALA195, ILE198, ILE209, ASP210, SER213
P11	ASN140, ASP141, CYS144, ASP300, LYS302, PRO328, TYR329, LEU330, GLU331, GLN332, TYR333	GLU81, ASN82, TYR128, TYR131, GLN132, ARG135, ASP162, LEU163, LYS164, ASP321
P12	HIS158, LYS224, SER225, ILE228, PRO315, ASN316, ARG318, ILE319, THR320, VAL321, GLU322	ARG77, PHE78, ARG79, TYR139, ALA143, ALA325, GLU326, ALA327, PRO328, PHE329
P13	GLN90, ILE91, ARG94, PHE346, THR347, PHE348	ASP20, ILE90, ARG91, ALA92, PRO93, GLN97, MET98, LYS99, ASP100, VAL101, TYR102
P14	–	PHE183, LEU184, MET199, LEU200, TYR233, LEU234, GLN236, LEU237, ASN238, TYR263
P15	–	ASN123, ASP124, CYS127, ASP283, LYS285, PRO311, TYR312, LEU313, GLU314, GLN315
P16	–	GLN17, GLU33, GLY34, ALA35, TYR36, GLY37, MET38, LYS55, ILE56, SER57

Table 3.

ERK1&2 protein pocket with surface area (Ų), volume (ų), and druggability score.

	ERK1 protein (PDB ID:4QTB)			ERK2 protein (PDB ID:5NHJ)
Pockets no.	Surface area (Å2)	Volume (Å3)	Druggability score	Surface area (Å2)	Volume (Å3)	Druggability score
P0	1183.93	993.86	0.81	870.93	768.77	0.84
P1	1119.89	852.54	0.84	500.22	365.82	0.55
P2	722.63	362.56	0.71	519.93	364.74	0.74
P3	525.43	303.23	0.56	445.8	264.64	0.57
P4	567.25	280.26	0.39	476.38	255.1	0.4
P5	294.19	274.75	0.48	433.47	235.01	0.46
P6	358.74	232.83	0.36	456.03	230.34	0.4
P7	454.31	212.74	0.52	415.18	217.86	0.44
P8	415.84	170.18	0.33	343.58	206.78	0.43
P9	340.53	160.58	0.21	430.57	177.92	0.29
P10	330.11	155.39	0.23	144.94	165.5	0.32
P11	345.07	139.14	0.17	387.53	164.29	0.25
P12	254.41	131.65	0.26	306.92	137.6	0.36
P13	234.64	101.95	0.2	281.03	130.69	0.23
P14	–	–	–	289.51	124.22	0.29
P15	–	–	–	386.3	124.1	0.16
P16	–	–	–	309.3	121.54	0.2

ERK inhibitors in cancer treatment

A growing number of ERK inhibitors are currently under investigation across various preclinical and clinical stages. Direct inhibition of ERK1/2 represents a promising therapeutic strategy, positioning it as a potentially “druggable” target within the MAPK pathway. This approach may offer a valuable alternative for treating cancers driven by RAS or BRAF mutations. In particular, patients who have developed resistance to RAF and/or MEK inhibitors—often due to reactivation of the pathway—may benefit from ERK1/2-targeted therapies.

Several small-molecule ERK1/2 inhibitors have been identified recently, including SCH772984, SCH900353²², ulixertinib (BVD-523)²³, GDC-0994²⁴ among others. These inhibitors have shown potential in overcoming acquired resistance and suppressing downstream ERK signalling.

ERK inhibitors under clinical trial

Clinical trials have been conducted to evaluate the efficacy, safety, and therapeutic potential of various ERK1/2 inhibitors. These studies have demonstrated that ERK inhibitors exhibit notable selectivity and effectiveness, particularly in tumours driven by RAS or BRAF mutations. Importantly, ERK inhibitors may provide therapeutic benefit in patients who have developed resistance to RAF or MEK inhibitors, by targeting downstream signalling and mitigating pathway reactivation.

1. BVD-523 (Ulixertinib): The first small-molecule ERK1/2 kinase inhibitor to enter clinical trials was ulixertinib (also known as BVD-523 or VRT752271) (Table 4). This orally bioavailable pyridine–pyrrole derivative is currently under clinical investigation for the treatment of non-Hodgkin lymphomas, acute myelogenous leukaemia (AML), advanced solid tumours, and pancreatic cancers²⁵. Ulixertinib functions as a potent, selective, and reversible ATP-competitive inhibitor of ERK1/2, with Ki values of 0.3 nM for ERK1 and 0.04 nM for ERK2, respectively²⁶. In preclinical studies, ulixertinib demonstrated strong antitumour activity across various BRAF- and RAS-mutant cell lines^23,27. In particular, it showed high efficacy in a Colo205 human colorectal cancer xenograft model, exhibiting a Ki of 0.04 ± 0.02 nM against ERK2. Additionally, ulixertinib effectively suppressed the proliferation of multiple human tumour cell lines harbouring activating mutations in the MAPK signalling pathway²⁶. In vivo, ulixertinib significantly inhibited tumour growth in KRAS-mutant colorectal and pancreatic cancer models, as well as in BRAF-mutant melanoma and colorectal xenografts. It is currently undergoing Phase I/II clinical development for patients with advanced solid tumours²⁸.

Table 4.

ERK Inhibitors in clinical trial with chemical structure and clinical progression.

SR. no.	Name	Chemical structure	Clinical progression	References
1.	BVD-523 (Ulixertinib)		Phase I/II	23,51
2.	MK-8353		Phase I	31
3.	GDC-0994		Phase I	24
4.	LY-3214996		Phase I	38
5.	CC-90003		Phase I	43
6.	BDBM418230		Phase I	33
7.	KO-947		Phase I	46
8.	ASN007		Phase I	47
9.	LTT462		Phase I	32

2. MK-8353: MK-8353 (formerly SCH900353) (Table 4) is an indazole–pyrrolidine derivative developed through structure-based drug design. It is a reversible, orally bioavailable ERK1/2 inhibitor characterised by high kinase selectivity and potent inhibitory activity^29,30. This compound was synthesised by Morris et al., who reported IC₅₀ values of 4 nM for ERK1 and 1 nM for ERK2, indicating strong target affinity³¹. A Phase I clinical study of SCH900353 began in 2011 and concluded in 2014³². The compound showed promising antitumour activity in patients with BRAF^V600-mutant melanoma and was well-tolerated at doses up to 400 mg administered twice daily. MK-8353 demonstrated broad-spectrum anticancer activity, including in tumour cells with resistance to MAPK pathway inhibitors and those harbouring BRAF or RAS mutations^31,33,34. Preclinical evaluations revealed that MK-8353 was effective against a variety of colorectal, melanoma, and pancreatic cancer cell lines, as well as their respective xenograft models, particularly those containing BRAF, KRAS, or NRAS mutations. Notably, MK-8353 also exhibited efficacy against tumour cells with clinically relevant mechanisms of resistance to BRAF or MEK inhibitors, including BRAF^V600E overexpression, loss of the RAS-binding domain in N-terminal BRAF splice variants, acquired RAS mutations, acquired MEK1 mutations, and ectopic expression of various MEK1 mutants³³.

3. GDC-0994/Ravoxertinib: GDC-0994 is a pyrazole amino-pyrimidine derivative (Table 4) and a small-molecule, highly selective, orally bioavailable, reversible ATP-competitive ERK1/2 inhibitor with demonstrated promising in vitro and in vivo efficacy^35,36. It is currently being evaluated in early-phase clinical trials, both as a monotherapy and in combination with cobimetinib, for the treatment of advanced or metastatic solid tumours. GDC-0994 exhibits strong and selective inhibition of ERK1/2, with IC₅₀ values of 6.1 nM for ERK1 and 3.1 nM for ERK2, respectively. These data highlight its potential utility in targeting MAPK pathway-driven malignancies²².

4. Temuterkib (LY3214996): It is selective ERK1/2 Inhibitor with promising antitumour activity. Temuterkib (formerly LY3214996) (Table 4) is a novel, highly selective small-molecule inhibitor of ERK1 and ERK2, currently undergoing Phase I clinical trials. In biochemical assays, it demonstrated IC₅₀ values of 5 nM for both ERK1 and ERK2, indicating potent inhibition³⁷. Preclinical studies have shown that intermittent dosing of temuterkib leads to robust antitumour activity in xenograft models of RAS-mutant lung cancer. In combination therapy settings, LY3214996 has consistently exhibited synergistic efficacy and was well-tolerated in KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer xenograft models^38,39. Temuterkib significantly reduced levels of phosphorylated RSK1 (p-RSK1)—a downstream ERK target—in cancer cell lines harbouring RAS and BRAF mutations, indicating effective pathway suppression. Furthermore, in various cancer models characterised by MAPK pathway alterations, temuterkib showed strong antitumour efficacy^38,40.

5. CC-90003: CC-90003 (Table 4) is a covalent, irreversible inhibitor of ERK1/2 that demonstrated promising antitumour activity in preclinical studies and entered Phase I clinical trials. It exhibits high kinase selectivity, as shown in a 258-kinase biochemical screen, with IC₅₀ values ranging from 10 to 20 nM. In a patient-derived xenograft (PDX) model of lung cancer, the combination of CC-90003 with docetaxel resulted in complete tumour regression and prevention of tumour recurrence following cessation of treatment. This therapeutic effect was associated with modulation of tumour stem cell reprogramming, supported by alterations in a stemness-related gene network⁴¹. Despite its promising preclinical profile, the clinical development of CC-90003 was discontinued, as the maximum tolerated dose (MTD) failed to produce acceptable clinical outcomes. The corresponding clinical trial (NCT02313012) was officially terminated for this reason^42,43.

6. BDBM418230: A potent dual ERK1/2 Inhibitor identified by fragment-based design. (2 R)-2–(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1–(3-methylphenyl)ethyl]propanamide (also known as BDBM418230) is an aminopyrimidine–isoindolinone derivative developed by Astex Pharmaceuticals (Table 4). This compound was discovered through a fragment-based drug discovery approach, as reported by Heightman et al.³³. BDBM418230 demonstrated potent inhibitory activity against ERK2, with an IC₅₀ of 3 nM. It also inhibited the proliferation of BRAF^V600E-mutant A375 melanoma cells and Colo205 colon cancer cells, with IC₅₀ values of 4.9 nM and 7.5 nM, respectively. Mechanistically, the compound effectively blocked the phosphorylation of ERK and its downstream substrate RSK, indicating dual inhibition of ERK1/2 signalling pathways. In comparison, the well-known dual ERK1/2 inhibitor SCH772984 suffers from a poor dissociation rate and short residence time⁴⁴, which limits its pharmacodynamics efficacy. Additionally, SCH772984 did not exhibit strong in vivo antitumour activity when administered orally or intraperitoneally⁴⁵.

7. KO-947: KO-947 is a highly potent small-molecule inhibitor targeting ERK1/2, with demonstrated activity in cancers harbouring BRAF, NRAS, and KRAS mutations (Table 4). A defining feature of KO-947 is its prolonged target residence time and high potency in cellular engagement, which contribute to its sustained inhibitory effects in both in vitro and in vivo models.

This long-lasting interaction with ERK1/2 enhances its therapeutic potential, particularly in malignancies characterised by constitutive MAPK pathway activation, and may offer advantages over inhibitors with shorter duration of action⁴⁶.

8. ASN007: ASN007 (Table 4) is an effective, targeted small-molecule ERK1/2 inhibitor characterised by its prolonged residence time at the target site, contributing to sustained pathway inhibition. It has demonstrated promising in vitro antitumour activity, particularly in cancer models with RAS and BRAF mutations⁴⁷ In xenograft studies, ASN007 significantly suppressed tumour growth in these genetically defined models. Notably, ASN007 has shown synergistic efficacy when used in combination with PI3K inhibitors, both in vitro and in vivo, suggesting a potential combinatorial strategy to overcome resistance mechanisms associated with MAPK and PI3K pathway crosstalk⁴⁸. ASN007 is currently undergoing evaluation in human clinical trials (ID: NCT03415126) and may represent a promising therapeutic alternative for RAS-mutated malignancies, either as a monotherapy or in combination with other targeted agents⁴⁹.

9. LTT462: LTT462 is a small-molecule ERK1/2 inhibitor currently under clinical development (Table 4). It has demonstrated promising preclinical antitumour activity in xenograft models and in various cancer cell lines with MAPK pathway activation. A first-in-human Phase I clinical trial (ID: NCT02711345) is underway to evaluate the safety, tolerability, and pharmacokinetics of LTT462 in patients with advanced solid tumours harbouring MAPK pathway alterations. Additionally, a combination strategy using LTT462 with LXH254, a pan-RAF inhibitor, is being assessed in a separate trial (NCT02974725) to explore synergistic therapeutic effects in treatment-resistant cancers³². These studies aim to determine the clinical potential of LTT462 as either a monotherapy or in combination regimens for MAPK-driven malignancies⁵⁰.

Recent advancements in ERK inhibitors

1. AZD0364 (Tizaterkib): AZD0364 (also known as Tizaterkib) is a dihydroimidazopyrazinone-based compound developed and characterised as an antitumour agent by Ward et al.⁴. In in vitro studies, AZD0364 demonstrated potent and selective inhibition of ERK1/2, leading to significant suppression of tumour cell growth, survival, and metastatic potential. Specifically, AZD0364 effectively inhibited the proliferation of KRAS-mutant tumour cell lines including A549, H2122, H2009, and Calu6 (Table 5). Importantly, combination therapy with AZD0364 and the MEK inhibitor selumetinib further enhanced tumour growth inhibition, indicating a synergistic effect. This combinatorial approach not only showed improved therapeutic efficacy but also has the potential to delay or prevent the development of resistance associated with MAPK pathway reactivation. Additionally, it may help to reduce treatment-related adverse effects and enhance patients’ quality of life, making it a promising strategy for MAPK-driven malignancies^52,53.

Table 5.

ERK inhibitors in pre-clinical trial with chemical structure and their stage of progression.

SR. no.	Name	Chemical structure	References
1.	AZD0364		4,52
2.	Norathyriol		55
3.	FR180204		56
4.	3-(2-Aminoethyl)-5-(4-ethoxybenzylidene)-1,3-thiazolidine-2,4-dione (Compound 76)		77
5.	VTX-11e		57
6.	AEZS-131 & AEZS-136	-	69,70
7.	(s)-14k	-	73
8.	Mono-fluorocyclopentanol		76
9.	N-(2-((2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (CC-90003)		67
10.	SF-3-030		82
11.	DEL-22379		83
12.	(R)-1-(3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea		86
13.	(R)-3-Methyl-7-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one		87
14.	(1E,2Z)-N’-nitro-2-((5-(3-nitrophenyl)furan-2-yl)methylene)hydrazine-1-carboximidamide & (E)-5-(4-((4-bromobenzyl)oxy)-3-methoxybenzylidene)imidazolidine-2,4-dione		85
15.	FR148083/hypothemycin		89,92

2. Norathyriol: Li et al. screened a Chinese natural compound library and identified norathyriol as a metabolite of mangiferin, a bioactive compound found in mango (Table 5) Norathyriol functions as a specific ATP-competitive inhibitor of ERK1/2 and has demonstrated potential in the prevention of UVB-induced non-melanoma and melanoma skin cancers. Mechanistically, norathyriol inhibits UVB-induced phosphorylation of the MAPK cascade, particularly suppressing ERK1/2 kinase activity. Structural studies, including a co-crystal structure with ERK2, confirmed direct binding of norathyriol to the kinase. The xanthone moiety of norathyriol acts as an adenine mimetic, forming a hydrogen bond within the ATP-binding pocket of ERK2, thereby stabilising the inhibitor-protein complex^54,55.

3. FR180204: FR180204 is a small-molecule inhibitor identified as a potent ATP-competitive inhibitor of ERK1/2 (Table 5)⁵⁶. Lineweaver–Burk kinetic analysis revealed that ATP binding to ERK1/2 is facilitated by an interaction between the side-chain amino group of Lys54 and the phosphoric acid moiety of ATP. Importantly, the hydrogen bond formed between FR180204 and the gatekeeper residue Gln105 plays a critical role in kinase selectivity, offering a structural basis for its specificity. The discovery and characterisation of FR180204 underscore the feasibility and effectiveness of targeting key protein–ligand interactions in small-molecule drug design for ERK pathway modulation⁵⁷.

4. 3–(2-Aminoethyl)-5–(4-ethoxybenzylidene)-1,3-thiazolidine-2,4-dione (Compound 76): This ERK1/2 inhibitor, identified using computer-assisted drug design (CADD) tools, targets the substrate interaction domain of ERK1/2 rather than the ATP-binding site (Table 5)⁵⁸. It was shown to suppress phosphorylation of downstream ERK targets such as ribosomal S6 kinase (Rsk-1) and ETS-like gene 1 (Elk-1), thereby inhibiting the proliferation of HeLa cervical cancer and A549 lung cancer cells. The D-recruitment site (DRS) of ERK, formed by aspartate residues, plays a critical role in recognising substrates with D domains. This compound, 3–(2-aminoethyl)-5–(4-ethoxybenzylidene)-1,3-thiazolidine-2,4-dione, was found to act as a DRS-targeting inhibitor, capable of binding a polar cleft within the docking site^59–61. Although it exhibited only micro molar-range affinity for ERK1/2 and was therefore unsuitable as a therapeutic agent in its initial form, it provided a valuable lead structure. Subsequent development of structurally optimised analogues based on this scaffold has opened a potential path towards the discovery of more potent and substrate-specific ERK1/2 inhibitors^62–64.

5. VTX-11e: VTX-11e, a pyrazolyl–pyrrole-based compound developed by Vertex Pharmaceuticals, is a micromolar-range ERK kinase inhibitor noted for its potency and selectivity against ERK2 (Table 5)⁵⁷. Early crystallographic studies conducted by Aronov et al. provided insight into the binding mode of these inhibitors in complex with ERK2, laying the groundwork for rational drug design. Despite the excellent kinase selectivity profile, the pyrazolyl–pyrrole scaffold suffered from limited cellular efficacy, which emerged as a major limitation⁶⁵. To overcome this, researchers pursued structure-guided optimisation, aiming to enhance cellular activity by replacing the pyrazole ring with a pyrimidine moiety. This effort led to the development of pyrimidinyl–pyrrole derivative 11e, a sub-nanomolar, highly selective ERK2 inhibitor that exhibited potent cellular activity and oral bioavailability^66,67. The discovery of 11e underscores the importance of integrating crystallographic data with medicinal chemistry in the development of next-generation ERK inhibitors.

6. AEZS-131 & AEZS-136: AEZS-131 (Table 5) is a selective, orally bioavailable, ATP-competitive ERK inhibitor developed by Aeterna Zentaris, Inc.⁶⁸. It has demonstrated high selectivity for ERK1/2 over other kinases, particularly in triple-negative breast cancer (TNBC) models. Preclinical studies revealed that AEZS-131 exhibits potent cytotoxic effects and induces G1 phase cell cycle arrest in cancer cells. Currently, AEZS-131 is being investigated in TNBC cell lines harbouring MAPK pathway mutations, highlighting its potential in treating MAPK-driven malignancies⁶⁹. A closely related compound, AEZS-136, has also shown promise as a potent ERK1/2 inhibitor, with potential efficacy against tumours harbouring upstream MAPK mutations, such as in RAS or RAF genes⁷⁰.

7. (S)-14k: A series of tetrahydropyrido-pyrimidine ERK1/2 antagonists were identified through structure-based drug design, as reported by Blake et al. These compounds exhibited high potency and selectivity in both enzymatic and cell-based assays, but their advancement as therapeutic agents was limited due to poor pharmacokinetic (PK) properties^71,72. Subsequent optimisation efforts led to the discovery of (S)-14k, a highly potent and selective ERK1/2 inhibitor (Table 5)⁷³. Although (S)-14k was selected for further preclinical evaluation, its predicted human dose, based on in vivo efficacy studies and PK parameters, was determined to be unacceptably high. To address this limitation, additional preclinical PK/PD studies and efficacy trials were undertaken with the goal of reducing drug clearance and enhancing exposure, thereby improving the feasibility of achieving therapeutic coverage⁷⁴.

8. Mono-fluorocyclopentanol: Bogdanoff et al. employed focused screening and structure-based drug design (SBDD) strategies to optimise tetrahydro-pyrazolopyridine scaffolds, aiming to develop compact and selective ERK2 inhibitors. This led to the generation of tetrahydropyrrole–phthalazinone derivatives, which demonstrated significant improvements in potency, lipophilicity, and in vitro metabolic stability, achieved through iterative scaffold hybridisation and optimisation⁷⁵. However, further development of these compounds was hindered by a high extraction ratio (ER) in rat and human liver microsomes, which posed challenges for systemic drug exposure and clinical translation. To overcome this limitation, a fluorinated cyclopentanol side chain was introduced, resulting in a novel compound featuring a mono-fluorocyclopentanol moiety (Table 5). This modification significantly reduced the human microsomal ER, thereby enhancing metabolic stability and making the compound more suitable for continued preclinical development⁷⁶.

9. CC-90003: CC-90003 [N-(2-((2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)-pyrimidin-4-yl)amino)phenyl)acrylamide] is a selective, irreversible covalent inhibitor of ERK1/2, discovered through a combination of high-throughput screening and structure-based drug design (SBDD), as reported by Ward et al.⁷⁷. This compound emerged from a series of covalent inhibitors optimised for potency, selectivity, and pharmacological properties. After multiple rounds of structural optimisation, several analogues with in vitro potency and selectivity comparable to clinically evaluated non-covalent ERK1/2 inhibitors were identified. Importantly, these covalent inhibitors—including CC-90003—demonstrated superior ligand efficiency (LE) and favourable ligand lipophilicity profiles, making them attractive candidates for further development (Table 5)^78,79. The progress in rational design of targeted covalent inhibitors (TCIs) such as CC-90003 underscores a growing interest in covalent inhibition strategies for ERK1/2. With continued advancement, these compounds may offer advantages in durability of response, overcoming resistance, and improved dosing profiles, potentially rejuvenating the field of covalent ERK inhibitor development⁸⁰.

10. SF-3–030: Activated ERK1/2 can phosphorylate over 100 substrate proteins, contributing to a wide range of cellular processes. This complexity presents significant challenges for the development of small-molecule ERK1/2 inhibitors, as these drugs must navigate and potentially disrupt a network of protein–substrate interactions. To elucidate the molecular interactions between ERK1/2 and its substrates and inhibitors, the Shapiro group employed structure-based interaction ligand-synchronised saturation (SILCS) analysis^81,82. This approach enabled the identification of contact sites on the ERK1/2 protein surface that interact with small-molecule inhibitors, using both computational modelling and experimental validation. Among the series of compounds evaluated, those bearing a thienyl benzenesulfonate scaffold were structurally optimised, ultimately yielding SF-3–030, a selective ERK1/2 inhibitor (Table 5). SF-3–030 demonstrated potent biological activity by inhibiting, ERK1/2-mediated immediate early gene (IEG) promoter activity ERK2-dependent phosphorylation of c-Fos in vitro EGF- or PMA-induced expression of IEG proteins, as shown through 3D fragment binding probability maps (FragMaps). Importantly, SF-3–030 was shown to inhibit the growth of melanoma cells resistant to clinically approved kinase inhibitors, suggesting its potential utility in overcoming therapeutic resistance⁸³. These findings support SF-3–030 as a novel therapeutic candidate, particularly for cancers with inherent resistance to existing MAPK pathway inhibitors.

11. DEL-22379: Casar et al. reported a novel mechanism for targeting the MAPK pathway by inhibiting ERK dimerisation, without affecting ERK phosphorylation levels. This finding introduced a highly specific therapeutic strategy for treating MAPK-driven malignancies, offering an alternative to conventional inhibitors that target ERK catalytic activity⁸⁴. To identify small molecules capable of selectively blocking ERK dimerisation, the researchers developed a native gel electrophoresis-based screening method. Through screening and optimisation, the team discovered DEL-22379, a 3-arylene-2-oxindole derivative that emerged as a potent and selective ERK dimerisation inhibitor (Table 5). Importantly, DEL-22379 inhibits ERK dimer formation while preserving ERK kinase catalytic activity, thereby disrupting downstream signalling without broadly interfering with ERK’s enzymatic function. Preclinical studies demonstrated the anticancer efficacy of DEL-22379 in xenograft models of BRAF- and RAS-mutant colorectal cancers, where it reduced tumour growth, incidence, and metastasis. Furthermore, by targeting dimerisation rather than kinase activity, DEL-22379 minimised off-target effects and was associated with reduced toxicity. This suggests that ERK dimerisation inhibitors, such as DEL-22379, could be developed into well-tolerated, long-term cancer therapies, especially for tumours with constitutive MAPK pathway activation⁸⁵.

12. (R)-1–(3-(2-Methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3–(1-phenylethyl) urea: The dual ERK1/2 inhibitor SCH772984 is known for its high potency and selectivity, but its high molecular weight (MW = 588 Da) results in low ligand efficiency (LE = 0.29), potentially compromising its drug-likeness and pharmacokinetic properties⁷⁸. In an effort to address these limitations, Lim et al. explored structural modifications focused on reducing molecular size while maintaining potency. By incorporating a novel 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)urea scaffold, they developed a series of compounds through structure–activity relationship (SAR) optimisation. This approach led to the identification of a new ERK1/2 inhibitor (Table 5) that demonstrated, improved ligand efficiency (LE = 0.46 vs. 0.29 for SCH772984), moderate aqueous solubility, reasonable polarity profile, enhanced kinase selectivity. Notably, unlike SCH772984, the optimised compound did not inhibit ERK1/2 phosphorylation, suggesting a distinct mechanism of inhibition, possibly downstream of activation. In preclinical evaluation, this compound exhibited substantial tumour regression in BRAF^V600E-mutant xenograft models, affirming its potential as an antineoplastic agent⁸⁶.

13. (R)-3-Methyl-7–(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one: Researchers at AstraZeneca investigated the development of high-quality, potent, and selective reversible ERK1/2 inhibitors using an in-house kinase selectivity panel. Through this screening, they identified a promising class of compounds featuring a pyrimidinyl–pyrrolidine scaffold with a lactam nucleus, which exhibited strong dual inhibition of ERK1 and ERK2⁷⁷. In vitro assays confirmed the compound’s potent inhibitory activity against ERK1/2, and it elicited favourable antitumour responses in xenograft models. Structural studies further supported its efficacy; X-ray crystallography revealed a binding conformation consistent with known ERK-selective inhibitors, distinguishing it from broader dual-mechanism inhibitors⁸⁷. These findings validate the pyrimidinyl–pyrrolidine scaffold as a viable pharmacophore for the design of selective, reversible ERK1/2 inhibitors, and highlight its potential in further anticancer drug development.

14. (1E, 2Z)-N’-Nitro-2-((5–(3-nitrophenyl)furan-2-yl)methylene)hydrazine-1-carboximidamide & (E)-5–(4-((4-bromobenzyl)oxy)-3-methoxybenzylidene)-imidazolidine-2,4-dione: Using the three-dimensional structure of the unphosphorylated, inactive ERK2, Hancock et al. pioneered the identification of the first ATP-independent ERK1/2 inhibitors. Employing computer-assisted drug design (CADD) and structure-guided screening of the ChemBridge chemical library, the team extended their search to include the phosphorylated ERK2 structure, leading to the discovery of inhibitors that specifically target the ERK docking domain. Among the most promising candidates identified were: (1E, 2Z)-N’-Nitro-2-((5–(3-nitrophenyl)furan-2-yl)methylene)hydrazine-1-carboximidamide (E)-5–(4-((4-bromobenzyl)oxy)-3-methoxybenzylidene)imidazolidine-2,4-dione. These compounds (Table 5) exhibited selective ERK inhibition, independent of ATP competition, and were validated through a range of bioassays. In vitro fluorescence quenching experiments demonstrated that both compounds bound directly to ERK2 with similar affinities, effectively inhibiting the phosphorylation of ERK downstream targets, including Elk-1 and Rsk-1. These findings introduce a novel class of ATP-independent ERK1/2 inhibitors that operate by disrupting protein–protein interactions at the docking domain, offering a promising therapeutic alternative to overcome resistance associated with ATP-site inhibitors^58,88.

15. FR148083 & hypothemycin: FR148083, a derivative of benzoxacyclo tetradecylpyridine, was isolated by Ohori et al. from fermentation broth and identified as a selective ERK2 inhibitor (Table 5)⁸⁹. Structure–activity relationship (SAR) studies revealed that FR148083 functions as an irreversible ERK inhibitor, owing to its α,β-unsaturated ketone moiety (a Michael acceptor) which forms a covalent bond with Cys166 in the ERK2 active site. X-ray crystallographic analysis of the ERK2–FR148083 complex demonstrated that the compound binds to the ATP-binding site via multiple hydrogen bonds and hydrophobic interactions, precisely positioning the Michael acceptor near Cys166 to facilitate covalent bond formation⁹⁰. This unique mechanism of molecular recognition provides a valuable framework for the design of irreversible ERK inhibitors for targeted cancer therapy. Similarly, hypothemycin, a natural resorcylic acid lactone, possesses a cis-enone structure capable of undergoing a Michael addition reaction with the thiol group of cysteine residues in kinase targets. Structural studies of the ERK2–hypothemycin complex confirmed that hypothemycin mimics ATP through a network of hydrogen bonding and hydrophobic contacts, localising it at the ATP-binding site⁹¹. These findings also highlighted how the external conformation of the DFG motif contributes to the specificity and reactivity of covalent inhibitors. The pharmacophores and covalent traps observed in these complexes provide a rational structural basis for designing irreversible kinase inhibitors that covalently target the ATP-binding pocket, offering a powerful strategy for the development of next-generation anticancer agents⁹². Different ERK clinical drugs with combinations in different cancer treatments are depicted in Table 6.

Table 6.

Combination drug therapy of clinically ERK inhibitors.

Sl. no.	Drug (clinical trials)	Combination	Indication	Reference
1.	BVD-523	BRAF inhibitors	Synergistic anti-proliferative effects	23 , 93–95
2.	GDC-0994	MEK inhibitors	Mutations of the MAPK upstream pathways	32 , 96 , 97
3.	CC-90003	Docetaxel	Prevented tumour regrowth after cessation of treatment in a PDX model of lung cancer	41

In recent years, a wide array of novel scaffolds and structural motifs has been synthesised as ERK1/2 inhibitors, with their biological activity extensively evaluated against various cancer cell lines. However, in the present study, we focused on identifying the most potent compounds from both synthesised and reported series, based primarily on their in vitro antiproliferative activity. The chemical structures of these selected lead compounds are illustrated in Figure 4, while a detailed summary of their biological activity, target specificity, and potency across cancer models is provided in Table 7.

Figure 4.

 Chemical structure of most potent ERK inhibitors reported in literature.

Table 7.

Pin point of most potent ERK inhibitors reported in literature.

Cpd. no.	Derivatives	Cell line	Activity	Pinpoint	Ref.
01.	Pyrazole	MCF-7 PC-3	IC50 = 3.9 ± 0.076 µM	Cytotoxic effects on PC-3 and MCF-7 cancer cell lines	98
02.	Indazole	FaDu	IC50 = 2.78 µM	The high cytotoxic effect on FaDu cells	99
03.	Coumarin-dihydroquinoxaline	MGC-803 cells	IC50 = 11.7 nM to 395.9 nM	Inhibits tubulin polymerisation and ERK signalling pathway. Effective in the inhibition of MGC-803 cells Xenograft model.	100
04.	Pyrimidine	HCT116	IC50 = 8.04 ± 0.94 µmol	Inhibits cell proliferation and growth, and induced cell apoptosis.	101
05.	Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione	MCF-7 A375 SK-MEL-2 SK-HEP-1	IC50 = 2.04 µM	Excellent antiproliferative activity against multi-cancer cell lines. Induce cell apoptosis by increasing ROS production.	102
06.	Triazole-quinazolines	BT-20	IC50 = 24.6 μM	Induced G0/G1 stalling in BT-20 cells and a decrease in the S phase. Significant reduction of p-ERK1/2.	103
07.	Benzamide	FAK Hela HCT-116 MDA-MB-231	IC50 = 35 nM	Displayed highest inhibition of FAK and tumour cells. Inhibited the clone formation and migration of tumour cells, inducing apoptosis.	104
08.	Pyrimidine	MCF-7, HepG-2, HCT-116	IC50 = 2.96 μM	Displayed a significant G2/M phase arrest and induction of the apoptosis	105
09.	Benzimidazole	MGC-803 HGC-27 SGC-7901 GES-1	IC50 = 1.02 μM	It showed better activity against the tested cells. It also displayed the highly selectivity between the tested gastric cancer cell lines and normal cells.	106
10.	quinolinylnaphthalenedione	MOLT-4 NCI-H226 NCI-H460 U251 MALME-3M OVCAR-3	IC50 = 8.65 ± 1.4	Compound demonstrated broad spectrum antitumour activity against the nine tumour subpanels	107
11.	1,2,4-trisubstituted imidazolinone	P38αMAPK, ERK1, ERK2	IC50 = 25.0(ERK1), 3.2(ERK2)	Showed activity in the submicromolar range and were found to be more effective than sorafenib against breast cancer (MCF7 and T47D), melanoma (LOX IMVI and MDAMB-435), and prostate (PC3) cell lines with IC50 ranging from 0.05 to 0.99 µm. Highly selective to the same cancer cell lines as compared to normal Vero cells	108
12.	Imidazo[2,1-b]thiazole	COLO 205, NCIH460, MCF7, L132	IC50 = 0.476 μM	Suppressed ERK1/2 phosphorylation in a dose-dependent manner	109
13.	Quinolinylaminopyrimidines	A375P	IC50 = 0.57 μM	It inhibits melanoma cellproliferation through ERK kinase inhibition	110
14.	Thioflavone derivatives	HT1080	IC50 = 8.6 μM	It showed a more potent inhibitory effect than the corresponding oxygen compound (PD98059)	111
15.	Diarylamides 1,3,4-triarylpyrazole derivatives	LOX IMVI M14	IC50 = 0.36 mM	It showed the best potency against almost all the tested cell lines	112

Future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics

Despite significant advances in the development of ERK1/2 inhibitors, no ERK-targeted therapy has yet received FDA approval. To transition ERK inhibitors from preclinical stages to clinical success, several strategic directions must be pursued in future drug development.

Targeting resistance mechanisms included future ERK inhibitors must effectively function downstream of common oncogenic mutations such as those in RAS and RAF, including BRAF amplification, MEK1/2 mutations, and ERK feedback reactivation. Addressing these resistance pathways is crucial to overcome the limitations seen with current targeted therapies. The development of covalent, irreversible, or dual-pathway inhibitors can block compensatory survival signalling and limit tumour escape mechanisms.

Novel mechanisms of inhibition included a paradigm shift from traditional ATP-competitive inhibitors, which often suffer from limited selectivity and high toxicity, is essential. The focus should move towards: Allosteric inhibitors, which bind outside the ATP-binding pocket and offer increased target selectivity.

Many potent ERK inhibitors have failed clinically due to high molecular weight, poor oral bioavailability, and suboptimal pharmacokinetics. Next-generation ERK inhibitors should be designed with improved drug-like characteristics having high ligand efficiency (LE), favourable lipophilicity (LogP), oral bioavailability and plasma stability. These features will maximise tumour selectivity and minimise systemic toxicity.

Rational scaffold design and integration of structure-based drug design (SBDD) using high-resolution crystal structures of ERK1/2 (both phosphorylated and unphosphorylated) will be essential for core scaffold optimisation. Rational design of hybrid molecules that merge key pharmacophores from earlier ERK inhibitors such approaches can improve both potency and selectivity, while enhancing physicochemical and pharmacokinetic profiles.

Combination therapies and synthetic lethality approach such as monotherapies with ERK inhibitors may be insufficient for long-term efficacy. Therefore, combination therapies with MEK or RAF inhibitors (to delay resistance). PI3K, CDK4/6, or immune checkpoint inhibitors can enhance treatment efficacy and tackle pathway redundancies. Synthetic lethality-based strategies can further increase cancer cell-specific killing while sparing normal cells.

Addressing the complexity of ERK biology included he multifunctional role of ERK in both nuclear and cytoplasmic signalling necessitates a nuanced understanding of its biological functions. Future ERK inhibitors must not only block kinase activity but also consider subcellular localisation, feedback loops, and context-specific signalling to achieve therapeutic success.

To advance ERK inhibitors towards FDA approval and clinical use in cancer therapy, future drug development must embrace novel mechanisms of inhibition, improved pharmacological properties, and strategic combination regimens. A deeper understanding of ERK biology, coupled with innovative chemical design, holds promise for overcoming current therapeutic limitations and achieving long-term patient benefits.

Conclusion

Mutations and deregulation of protein kinases have been implicated in a wide array of human diseases, most notably cancer. Over the past few decades, kinases—particularly those within the MAPK signalling cascade—have emerged as pivotal therapeutic targets, driving the development of several kinase inhibitors. While the FDA has approved multiple BRAF and MEK inhibitors for clinical use, a persistent challenge remains: acquired drug resistance frequently emerges soon after treatment initiation, thereby diminishing therapeutic efficacy and underscoring the pressing need for next-generation MAPK pathway inhibitors.

This review emphasises the central role of ERK proteins (ERK1/2) within the MAPK pathway and their regulation during the transition from normal to oncogenic signalling. It underscores how detailed structural and functional analyses of ERKs have fuelled the discovery and rational design of novel small-molecule inhibitors targeting different facets of ERK signalling. Although many ERK-targeted inhibitors have demonstrated promising antitumour activity in preclinical and clinical studies, none have yet received FDA approval, reflecting the complexity of ERK biology and the ongoing need for therapeutic refinement.

In this context, we have presented a comprehensive overview of the molecular structure, regulatory mechanisms, and inhibitor binding dynamics of ERK1/2, along with a detailed examination of current ERK inhibitors, including both clinical development and those in advanced preclinical development. This review aims to serve as a valuable resource for researchers, offering critical insights into the design, development, and future potential of ERK-targeted therapies for improving clinical outcomes in cancer treatment.

Funding Statement

The APC was funded by King Abdullah University of Science and Technology, Thuwal, Jeddah, Saudi Arabia.

Disclosure statement

The authors report no conflicts of interest.

Data availability statement

Authors confirm that the data supporting the findings of this study are available within the article.