Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity

Bioorg Med Chem. 2024 Sep 1:111:117862. doi: 10.1016/j.bmc.2024.117862. Epub 2024 Jul 30.

Abstract

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Keywords: C797S; Drug discovery; EGFR.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Mutation*
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • ErbB Receptors
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • EGFR protein, human