Distal Covalent Targeting Suppresses Signaling of Oncogenic K-Ras(G13C) in Cancer Cells.

ABSTRACT: Oncogenic mutations of Ras are among the most common genetic alterations in human cancer, with an estimated disease burden of >3 million new patients per year worldwide. Despite widespread appreciation of the importance of Ras in cancer, direct binding ligands, which block downstream signaling, were not reported until 2013 due to the lack of obvious drug binding pockets in the protein. The clinically approved K-Ras inhibitors are mutant-selective as they rely on covalent recognition of the highly nucleophilic somatic cysteine residue of K-Ras(G12C). Recent preclinical reports of noncovalent K-Ras binding inhibitors have emerged, which lack mutant specificity and exhibit varying degrees of biochemical preference for mutant K-Ras over the wild-type. An adjacent glycine-13 mutation, p. G13C,

SUBMITTER: Zheng Q 

PROVIDER: S-EPMC12319893 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature