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Review
. 2025 Dec;40(1):2555510.
doi: 10.1080/14756366.2025.2555510. Epub 2025 Sep 10.

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

Vimlendu Kumar Sah  1 , Ankit Kumar Singh  1   2 , Adarsh Kumar  1 , Vineet Prajapati  1 , Amandeep Singh Kalsi  1 , Habibullah Khalilullah  3 , Mariusz Jaremko  4 , Abdul-Hamid Emwas  5 , Amita Verma  2 , Pradeep Kumar  1
Affiliations
Review

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

Vimlendu Kumar Sah et al. J Enzyme Inhib Med Chem. 2025 Dec.

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.

Keywords: ERK1/2; MAPK; cancer; clinical trials; pre-clinical.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Regulation of ERK1/2 in MAPK signalling cascade.
Figure 2.
Figure 2.
Structural insight of ERK1/2 protein.
Figure 2.
Figure 2.
Structural insight of ERK1/2 protein.
Figure 3.
Figure 3.
Structural insight of ERK1/2 protein with different pocket number.
Figure 4.
Figure 4.
Chemical structure of most potent ERK inhibitors reported in literature.
Figure 4.
Figure 4.
Chemical structure of most potent ERK inhibitors reported in literature.
See this image and copyright information in PMC

References

    1. Chhikara BS, Parang K.. Global cancer statistics 2022: the trends projection analysis. Chem Biol Lett. 2023;10(1):451–451.
    1. Wong K-K. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4(1):28–35. - PubMed
    1. Guo Y-J, Pan W-W, Liu S-B, Shen Z-F, Xu Y, Hu L-L.. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19(3):1997–2007. - PMC - PubMed
    1. Ward RA, Anderton MJ, Bethel P, Breed J, Cook C, Davies EJ, Dobson A, Dong Z, Fairley G, Farrington P.. Discovery of a potent and selective oral inhibitor of ERK1/2 (AZD0364) that is efficacious in both monotherapy and combination therapy in models of nonsmall cell lung cancer (NSCLC). J Med Chem. 2019;78(13):11004–11018. - PubMed
    1. Wortzel I, Seger R.. The ERK cascade: distinct functions within various subcellular organelles. Genes Cancer. 2011;2(3):195–209. - PMC - PubMed

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