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

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, particularly abundant in lung, colorectal, and pancreatic cancer, has not been targeted with an approved therapeutic molecule. Here, we report a series of targeted electrophiles designed to covalently modify Cys13 in K-Ras(G13C), overcoming the structural challenge posed by its shifted position relative to Cys12 in K-Ras(G12C). These inhibitors effectively alkylate K-Ras(G13C) in both GDP- and GTP-bound states, block effector interactions, and suppress the growth of K-Ras(G13C)-mutation cancer cell lines. Our findings expand the landscape of covalent K-Ras inhibitors beyond G12 mutations, providing a new therapeutic strategy for K-Ras(G13C)-driven cancers.