| Literature DB >> 32250617 |
Jay B Fell1, John P Fischer1, Brian R Baer1, James F Blake1, Karyn Bouhana1, David M Briere2, Karin D Brown1, Laurence E Burgess1, Aaron C Burns2, Michael R Burkard1, Harrah Chiang2, Mark J Chicarelli1, Adam W Cook1, John J Gaudino1, Jill Hallin2, Lauren Hanson1, Dylan P Hartley1, Erik J Hicken1, Gary P Hingorani1, Ronald J Hinklin1, Macedonio J Mejia1, Peter Olson2, Jennifer N Otten1, Susan P Rhodes1, Martha E Rodriguez1, Pavel Savechenkov1, Darin J Smith1, Niranjan Sudhakar2, Francis X Sullivan1, Tony P Tang1, Guy P Vigers1, Lance Wollenberg1, James G Christensen2, Matthew A Marx2.
Abstract
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.Entities:
Year: 2020 PMID： 32250617 DOI： 10.1021/acs.jmedchem.9b02052
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446