Thursday, August 25, 2022

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

Ziyang Zhang, Johannes Morstein, Andrew K. Ecker, Keelan Z. Guiley, and Kevan M. Shokat

Journal of the American Chemical Society 2022

DOI: 10.1021/jacs.2c05377

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.



Aryl Fluorosulfate Based Inhibitors that Covalently Target the SIRT5 Lysine Deacylase

Bolding, J..E., Martin-Gago, P., Rajabi, N., Gamon, L..F., Hansen, T..N., Bartling, C..R.O., Strømgaard, K., Davies, M..J. and Olsen, C..A. ...