Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.

ABSTRACT: The development of the KRAS G12C inhibitor sotorasib is a major advance toward drugging KRAS. However, the G12C mutation is only found in about 10% of KRAS-driven tumors. KRAS possesses several tyrosine amino acids that could provide alternative sites for covalent drug development. Here, a library of aryl sulfonyl fluorides identified 1 (SOF-436) as an inhibitor of KRAS nucleotide exchange by guanine exchange factor SOS₁ and KRAS binding to effector protein rapidly accelerated fibrosarcoma kinase (RAF). Tyr-64 is the major reaction site of 1 (SOF-436), although minor reaction at Tyr-71 is also observed. The fragment binds to the Switch II pocket of KRAS based on whole protein mass spectrometry, nucleotide exchange, effector protein binding, and nuclear magnetic resonance studies

SUBMITTER: Landgraf AD 

PROVIDER: S-EPMC12174728 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature