Jay B. Fell, John P. Fischer, Brian R. Baer, James F. Blake, Karyn Bouhana, David M. Briere, Karin D. Brown, Laurence E. Burgess, Aaron C. Burns, Michael R. Burkard, Harrah Chiang, Mark J. Chicarelli, Adam W. Cook, John J. Gaudino, Jill Hallin, Lauren Hanson, Dylan P. Hartley, Erik J. Hicken, Gary P. Hingorani, Ronald J. Hinklin, Macedonio J. Mejia, Peter Olson, Jennifer N. Otten, Susan P. Rhodes, Martha E. Rodriguez, Pavel Savechenkov, Darin J. Smith, Niranjan Sudhakar, Francis X. Sullivan, Tony P. Tang, Guy P. Vigers, Lance Wollenberg, James G. Christensen, Matthew A. Marx
J. Med. Chem., 2020
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.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @email@example.com on Mastodon
Saturday, April 11, 2020
Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
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Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...