Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors

J Med Chem. 2020 Jan 9;63(1):52-65. doi: 10.1021/acs.jmedchem.9b01180. Epub 2019 Dec 24.

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).

Publication types

  • News
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / 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
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / therapeutic use*
  • Rats
  • Structure-Activity Relationship

Substances

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

Associated data

  • ClinicalTrials.gov/NCT03600883