Drugging ERK1/2 in Cancer: A Glimpse of Small-Molecule Inhibitors.
The extracellular signal-regulated kinases 1 and 2 (ERK1/2) play central roles in the mitogen-activated protein kinase (MAPK) pathway and have emerged as critical regulators of tumorigenesis. Aberrant ERK1/2 signaling is frequently observed in cancers such as melanoma, pancreatic cancer, and colorectal cancer. This review outlines the historical milestones in ERK1/2 research, from their discovery and structural characterization to their identification as oncogenic drivers and therapeutic targets. We detail the ERK1/2 signaling network, highlighting key upstream regulators, including rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK), along with downstream substrates that mediate diverse oncogenic processes. Therapeutic approaches aimed at ERK1/2 currently fall into two main classes: small-molecule inhibitors with single-target specificity and those designed to simultaneously act on dual targets, along with combination therapies designed to overcome resistance and improve efficacy. Furthermore, we explore innovative approaches, including proteolysis-targeting chimeras (PROTACs), autophagy-targeting chimeras (AUTACs), and antibody-drug conjugates (ADCs), which offer promising avenues for selectively modulating ERK1/2 activity. By integrating mechanistic insights with clinical development trends, this review underscores the potential of ERK1/2-targeted therapies in precision oncology.