Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors

Bioorg Med Chem Lett. 2021 Nov 15:52:128406. doi: 10.1016/j.bmcl.2021.128406. Epub 2021 Oct 5.

Abstract

Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead.

Keywords: Covalent; EGFR; T790M/L858R.

MeSH terms

  • Acrylamides / chemistry
  • Acrylamides / pharmacology*
  • Afatinib / chemistry
  • Afatinib / pharmacology*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Acrylamides
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • osimertinib
  • Afatinib
  • EGFR protein, human
  • ErbB Receptors