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

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. 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. 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.