Ostrem JM,
Peters U,
Sos ML,
Wells JA,
Shokat KM.
*
University of California, San Francisco, USA
K-Ras(G12C) Inhibitors Allosterically Control GTP Affinity and Effector Interactions.
Nature 2013;
503: 548-551
DOI:
10.1038/nature12796
Key words
K-Ras - covalent inhibitors - acrylamides - Sotorasib
Significance
Mutations in the important regulatory signal transduction protein K-Ras are found
in approximately 25% of human cancers. Attempts to target this notorious GTPase resulted
in many failures and the protein became known as ‘the undruggable’. Shokat and co-workers
took advantage of the nucleophilic cysteine of the G12C mutant and developed acrylamide-based
inhibitors that bind covalently and irreversibly.
Comment
A library of nearly 500 acrylamides and vinyl sulfonamides was synthesized and tested
for K-Ras G12C inhibition. Various aromatic building blocks were combined with the
electrophilic portion using amide bond couplings. Based on these discoveries, many
companies continued their discovery programs towards K-Ras anticancer drugs. Amgen’s
Sotorasib became the first FDA-approved K-Ras G12C inhibitor in May 2021.
