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

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).

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 1 Pg. 52-65 (01 09 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 31820981 (Publication Type: News, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• Piperazines
• Pyridines
• Pyrimidines
• Pyrimidinones
• sotorasib
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, therapeutic use)
• Clinical Trials as Topic
• Dogs
• Drug Discovery
• Humans
• Isomerism
• Madin Darby Canine Kidney Cells
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Neoplasms (drug therapy)
• Piperazines (chemistry, pharmacology, therapeutic use)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics)
• Pyridines (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Pyrimidines (chemistry, pharmacology, therapeutic use)
• Pyrimidinones (chemistry, pharmacokinetics, therapeutic use)
• Rats
• Structure-Activity Relationship