Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR

Angew Chem Int Ed Engl. 2016 Aug 26;55(36):10909-12. doi: 10.1002/anie.201605011. Epub 2016 Aug 5.

Abstract

Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug-resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S.

Keywords: cancer; drug discovery; drug resistance; medicinal chemistry; structure-based drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Humans
  • Kinetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Molecular Docking Simulation
  • Phosphorylation
  • Point Mutation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • ErbB Receptors