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

Creators: Zhang, Ziyang; Morstein, Johannes^{1, 2}; Ecker, Andrew K.; Guiley, Keelan Z.; Shokat, Kevan M.

1. University of California, San Francisco
2. California Institute of Technology

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.

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Acknowledgement

We thank the staff at A.L.S. beamline 8.2.1 for help with X-ray data collection and processing. We thank Dr. D. Matthew Peacock for providing the recombinant K-Ras proteins used in Figure 2B. Z.Z. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2281-17). J.M. thanks the NCI for a K00 award (K00CA253758). A.K.E. is thankful for the support by the National Institute of General Medicine of the National Institutes of Health by the Kirschstein NRSA T32 award (5T32GM64337-20). K.Z.G. is a Damon Runyon-HHMI Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2399-20). K.M.S. acknowledges The Waxman Foundation, The Mark Foundation (SU2C), NIH 1R01CA244550, and the Howard Hughes Medical Institute.

Conflict of Interest

The authors declare the following competing financial interest(s): K.M.S., Z.Z. and J.M. are inventors on patents owned by UCSF covering K-Ras targeting small molecules. K.M.S. has consulting agreements for the following companies, which involve monetary and/or stock compensation: Revolution Medicines, Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Mitokinin, Nested, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Turning Point, Ikena, Initial Therapeutics, Vevo and BioTheryX.

Additional Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c05377.

Supporting Information Figures S1–S6, Supporting Information Tables S1–S3, experimental procedures and characterization data for new compounds (PDF)

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