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

Brian A Lanman, Jennifer R. Allen, John G. Allen, Albert K Amegadzie, Kate S. Ashton, Shon K. Booker, Jian Jeffrey Chen, Ning Chen, Michael J Frohn, Guy Goodman, David J Kopecky, Longbin Liu, Patricia Lopez, Jonathan D Low, Vu Ma, Ana Elena Minatti, Thomas T Nguyen, Nobuko Nishimura, Alexander J. Pickrell, Anthony B. Reed, Youngsook Shin, Aaron Siegmund, Nuria A. Tamayo, Christopher M Tegley, Mary C Walton, Hui-Ling Wang, Ryan P. Wurz, May Xue, Kevin C 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 Volak, Kevin H Wang, Douglas A. Whittington, Stephan G Zech, J. Russell Lipford, and Victor J. Cee

Journal of Medicinal Chemistry 2019

DOI: 10.1021/acs.jmedchem.9b01180

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).