Medicinal chemistry perspective of ERK1/2 inhibitors in cancer treatment: an updated patent review (2019-present).

Abstract

Introduction: The mitogen-activated protein kinase (MAPK) pathway also known as the RAS/RAF/MEK/ERK pathway is a vital intracellular signaling cascade that regulates apoptosis, differentiation, proliferation, and signal transduction.

Area covered: This review focuses on the critical role of ERK1/2 in the MAPK pathway and its implication in various cancers. It presents a detailed analysis of ERK1/2 inhibitors currently undergoing clinical evaluation, along with recently patented ERK1/2 inhibitors. The data were compiled by systematically searching databases including SciFinder, PubMed, Scopus, Google Scholar, and Google Patents using the keyword 'ERK' for the period 2019 to the present.

Expert opinion: Since 2019, several heterocyclic ERK1/2 inhibitors have shown promise in overcoming resistance within the MAPK cascade. However, detailed investigations into mutant versus wild-type ERK1/2 binding dynamics remain sparse, and the development of non-traditional approaches like PROTAC-mediated ERK degradation is still in its nascent stage. To successfully transition ERK1/2 inhibitors from bench to bedside, several strategic directions must be prioritized. First, overcoming resistance remains a critical challenge. Future ERK inhibitors must effectively target downstream components. Second, there is a pressing need to move beyond traditional ATP-competitive inhibitors. In addition, the pharmacological properties of ERK-targeting agents to enhance clinical efficacy and safety.