Tuesday, September 13, 2022

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 E. Minatti, Thomas T. Nguyen, Nobuko Nishimura, Alexander J. Pickrell, Anthony B. Reed, Youngsook Shin, Aaron C. 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 P. Volak, Kevin H. Wang, Douglas A. Whittington, Stephan G. Zech, J. Russell Lipford, and Victor J. Cee

Journal of Medicinal Chemistry 2020 63 (1), 52-65
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).


Aryl Fluorosulfate Based Inhibitors that Covalently Target the SIRT5 Lysine Deacylase

Bolding, J..E., Martin-Gago, P., Rajabi, N., Gamon, L..F., Hansen, T..N., Bartling, C..R.O., Strømgaard, K., Davies, M..J. and Olsen, C..A. ...