Drugging the Undruggable using Irreversible Covalent K-Ras G12C Inhibitors

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.

Publication History

Article published online:
18 August 2021