ml8b00382_si_001.pdf (617.76 kB)

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity

Download (617.76 kB)
journal contribution
posted on 07.11.2018, 00:00 by Jay B. Fell, John P. Fischer, Brian R. Baer, Joshua Ballard, James F. Blake, Karyn Bouhana, Barbara J. Brandhuber, David M. Briere, Laurence E. Burgess, Michael R. Burkard, Harrah Chiang, Mark J. Chicarelli, Kevin Davidson, John J. Gaudino, Jill Hallin, Lauren Hanson, Kenneth Hee, Erik J. Hicken, Ronald J. Hinklin, Matthew A. Marx, Macedonio J. Mejia, Peter Olson, Pavel Savechenkov, Niranjan Sudhakar, Tony P. Tang, Guy P. Vigers, Henry Zecca, James G. Christensen
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.