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.