1. Identification of the Clinical Development Candidate MRTX849 , a Covalent KRAS G12C Inhibitor for the Treatment of Cancer.
- Author
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Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, Brown KD, Burgess LE, Burns AC, Burkard MR, Chiang H, Chicarelli MJ, Cook AW, Gaudino JJ, Hallin J, Hanson L, Hartley DP, Hicken EJ, Hingorani GP, Hinklin RJ, Mejia MJ, Olson P, Otten JN, Rhodes SP, Rodriguez ME, Savechenkov P, Smith DJ, Sudhakar N, Sullivan FX, Tang TP, Vigers GP, Wollenberg L, Christensen JG, and Marx MA
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Drug Design, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Humans, Mice, Models, Molecular, Mutation, Proto-Oncogene Proteins p21(ras) chemistry, Proto-Oncogene Proteins p21(ras) genetics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors
- 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 KRAS
G12C 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.- Published
- 2020
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