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Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.

ABSTRACT: KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC9460778 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.

Zhang Ziyang Z Morstein Johannes J Ecker Andrew K AK Guiley Keelan Z KZ Shokat Kevan M KM

Journal of the American Chemical Society 20220824 35

<i>KRAS</i> mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other <i>KRAS</i> hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imi ...[more]

PMID: 36001446

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