Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 13, Pages 6679-6693Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b02052
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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 KRAS(G12C) is described.
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