2. Academic Validation
  3. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

  • J Med Chem. 2020 Jan 9;63(1):52-65. doi: 10.1021/acs.jmedchem.9b01180.
Brian A Lanman,  Jennifer R Allen,  John G Allen,  Albert K Amegadzie,  Kate S Ashton,  Shon K Booker,  Jian Jeffrey Chen,  Ning Chen,  Michael J Frohn,  Guy Goodman,  David J Kopecky,  Longbin Liu,  Patricia Lopez,  Jonathan D Low,  Vu Ma,  Ana E Minatti,  Thomas T Nguyen,  Nobuko Nishimura,  Alexander J Pickrell,  Anthony B Reed,  Youngsook Shin,  Aaron C Siegmund,  Nuria A Tamayo,  Christopher M Tegley,  Mary C Walton,  Hui-Ling Wang,  Ryan P Wurz,  May Xue,  Kevin C Yang,  Pragathi Achanta,  Michael D Bartberger,  Jude Canon,  L Steven Hollis,  John D McCarter,  Christopher Mohr,  Karen Rex,  Anne Y Saiki,  Tisha San Miguel,  Laurie P Volak,  Kevin H Wang,  Douglas A Whittington,  Stephan G Zech,  J Russell Lipford,  Victor J Cee
PMID: 31820981 DOI: 10.1021/acs.jmedchem.9b01180
Abstract

KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).

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