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

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

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2555510. doi: 10.1080/14756366.2025.2555510.
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

Affiliations

  • 1 Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India.
  • 2 Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, India.
  • 3 Department of Pharmaceutical Chemistry and Pharmacognosy, Qassim University, Saudi Arabia.
  • 4 Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
  • 5 Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
PMID: 40928301 DOI: 10.1080/14756366.2025.2555510
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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