Identification of Small-Molecule Inhibitors that Block the GTP-Binding Pocket of K-Ras and Other Members of the Ras Superfamily of Small GTPases.

ABSTRACT: RAS genes encode small GTPases essential for mammalian cell proliferation, differentiation, and survival. RAS gene mutations are associated with 20% to 30% of all human cancers. Based on earlier reports of extremely high Ras binding affinities for GTP, Ras proteins were previously considered undruggable. Using three independent techniques, we report binding affinities of K-Ras and several K-Ras mutants for GTP in the 250 to 400 nmol/L range, orders of magnitude lower than previously reported (∼10 pmol/L). This discovery suggests that K-Ras and other small-GTPase proteins may indeed be druggable targets. We identified more than 400 small molecules that compete non-covalently with GTP binding to K-Ras. Focusing on two inhibitors, we demonstrate the inhibition of K-Ras in downstream signaling

SUBMITTER: Carta L 

PROVIDER: S-EPMC12757722 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature