molecules of the month

compound 3

KRASG12R mutant-selective covalent inhibitor

privileged arginine-reactive functional group

from previously disclosed KRAS inhibitors

J. Am. Chem. Soc.

University of California San Francisco, San Francisco, CA

compound 3 chemical structure KRASG12R mutant-selective covalent inhibitor - University of California San Francisco, San Francisco, CA
5 mins read

Context. “Compound 3” (UCSF) is a covalent KRASG12R inhibitor used as a proof-of-concept for covalent arginine modification. KRAS is the first oncoprotein to be identified and is a well-known cancer-driving protein. As one of the most frequently mutated proteins in pancreatic and colorectal cancers, residues that are frequently mutated are known as mutant hot spots. The Shokat group has published a number of high-profile papers targeting KRAS mutants, including one targeting KRASG12S just last month. Here the group uses a cleverly designed reactive group that selectively engages with arginine, an uncommonly targeted amino acid, by using a reaction, first described in 1916, to target the arginine sidechain selectively. These advances in the field of targeting KRAS mutants come on the…

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