| Literature DB >> 30613331 |
Jay B Fell1, John P Fischer1, Brian R Baer1, Joshua Ballard1, James F Blake1, Karyn Bouhana1, Barbara J Brandhuber1, David M Briere2, Laurence E Burgess1, Michael R Burkard1, Harrah Chiang2, Mark J Chicarelli1, Kevin Davidson1, John J Gaudino1, Jill Hallin2, Lauren Hanson1, Kenneth Hee1, Erik J Hicken1, Ronald J Hinklin1, Matthew A Marx2, Macedonio J Mejia1, Peter Olson2, Pavel Savechenkov1, Niranjan Sudhakar2, Tony P Tang1, Guy P Vigers1, Henry Zecca1, James G Christensen2.
Abstract
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.Entities:
Year: 2018 PMID： 30613331 PMCID： PMC6295846 DOI： 10.1021/acsmedchemlett.8b00382
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345