A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.

ABSTRACT: Despite significant advancements in kinase-targeted therapy, the emergence of acquired drug resistance to targets such as KRAS and MEK remains a challenge. Extracellular-regulated kinase 1/2 (ERK1/2), positioned at the terminus of this pathway, is highly conserved and less susceptible to mutations, thereby garnering attention as a crucial therapeutical target. However, attempts to use monotherapies that target ERK1/2 have achieved only limited clinical success, mainly due to the issues of limited efficacy and the emergence of drug resistance. Herein, we present a proof of concept that extracellular-regulated kinase 5 (ERK5) acts as a compensatory pathway after ERK1/2 inhibition in triple-negative breast cancer (TNBC). By utilizing the principle of polypharmacology, we computationally desig

SUBMITTER: Xiao H 

PROVIDER: S-EPMC11842588 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature