2. Academic Validation
  3. Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

  • J Med Chem. 2020 Jul 9;63(13):6679-6693. doi: 10.1021/acs.jmedchem.9b02052.
Jay B Fell 1,  John P Fischer 1,  Brian R Baer 1,  James F Blake 1,  Karyn Bouhana 1,  David M Briere 2,  Karin D Brown 1,  Laurence E Burgess 1,  Aaron C Burns 2,  Michael R Burkard 1,  Harrah Chiang 2,  Mark J Chicarelli 1,  Adam W Cook 1,  John J Gaudino 1,  Jill Hallin 2,  Lauren Hanson 1,  Dylan P Hartley 1,  Erik J Hicken 1,  Gary P Hingorani 1,  Ronald J Hinklin 1,  Macedonio J Mejia 1,  Peter Olson 2,  Jennifer N Otten 1,  Susan P Rhodes 1,  Martha E Rodriguez 1,  Pavel Savechenkov 1,  Darin J Smith 1,  Niranjan Sudhakar 2,  Francis X Sullivan 1,  Tony P Tang 1,  Guy P Vigers 1,  Lance Wollenberg 1,  James G Christensen 2,  Matthew A Marx 2
Affiliations

Affiliations

  • 1 Array BioPharma Inc, 3200 Walnut Street, Boulder, Colorado 80301, United States.
  • 2 Mirati Therapeutics, 9393 Towne Centre Drive, Suite 200, San Diego, California 92121, United States.
PMID: 32250617 DOI: 10.1021/acs.jmedchem.9b02052
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 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.

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