Discovery of EGF Receptor Inhibitors That Are Selective for the d746-750/T790M/C797S Mutant through Structure-Based de Novo Design

Angew Chem Int Ed Engl. 2017 Jun 19;56(26):7634-7638. doi: 10.1002/anie.201703389. Epub 2017 May 22.

Abstract

Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.

Keywords: EGFR; drug discovery; inhibitors; kinases; structure-based design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • Drug Discovery*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Molecular Structure
  • Mutation*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Thermodynamics

Substances

  • Protein Kinase Inhibitors
  • ErbB Receptors