Identification and characterization of binders to a cryptic and functional pocket in KRAS.

ABSTRACT: RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12

SUBMITTER: Beyer KS 

PROVIDER: S-EPMC12672662 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature