Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

J Med Chem. 2019 Aug 8;62(15):7302-7308. doi: 10.1021/acs.jmedchem.9b00576. Epub 2019 Jul 23.

Abstract

Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC50 of 27.5 nM against the EGFRL858R/T790M/C797S mutant, while being a significantly less potent for EGFRWT (IC50 > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray / methods
  • Drug Design*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Molecular Docking Simulation / methods
  • Mutation / drug effects
  • Mutation / physiology*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology
  • Structure-Activity Relationship

Substances

  • Pyridones
  • EGFR protein, human
  • ErbB Receptors