Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile
Ziyang Zhang, Johannes Morstein, Andrew K. Ecker, Keelan Z. Guiley, Kevan M. Shokat
Abstract
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.
Topics & Concepts
ChemistryElectrophileMutantSmall moleculeArginineCovalent bondStereochemistryNucleophileKRASMoleculeCombinatorial chemistryBiochemistryAmino acidMutationGeneOrganic chemistryCatalysisProtein Kinase Regulation and GTPase SignalingEnzyme function and inhibitionBiochemical and Molecular Research