Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.

By B. Lanman, Jennifer R. Allen, J. Allen, A. Amegadzie, K. Ashton, S. Booker, J. Chen, N. Chen, M. Frohn, G. Goodman and 34 more. Journal of Medicinal Chemistry, 2019

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KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target, however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in Phase I clinical trials (NCT03600883).

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/12664cbef30a36e2c744cbcf09df7fa5a08d7b91