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Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors

2019; American Chemical Society; Volume: 63; Issue: 1 Linguagem: Inglês

10.1021/acs.jmedchem.9b01180

1520-4804

Brian A. Lanman, Jennifer R. Allen, John G. Allen, Albert Amegadzie, Kate S. Ashton, Shon K. Booker, Jian Jeffrey Chen, Ning Chen, Michael Frohn, Guy Goodman, David J. Kopecky, Longbin Liu, Patricia López, Jonathan D. Low, Vu Ma, Ana Minatti, Thomas T. Nguyen, Nobuko Nishimura, Alexander J. Pickrell, Anthony B. Reed, Youngsook Shin, Aaron C. Siegmund, Nuria Tamayo, Christopher M. Tegley, Mary C. Walton, Hui-Ling Wang, Ryan P. Wurz, May Xue, Kevin Yang, Pragathi Achanta, Michael D. Bartberger, Jude Canon, L. Steven Hollis, John D. McCarter, Christopher Mohr, Karen Rex, Anne Y. Saiki, Tisha San Miguel, Laurie P. Volak, Kevin H. Wang, Douglas A. Whittington, Stephan G. Zech, J. Russell Lipford, Victor J. Cee,

Microtubule and mitosis dynamics

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).