Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors

Bioorg Med Chem. 2016 Nov 1;24(21):5505-5512. doi: 10.1016/j.bmc.2016.09.001. Epub 2016 Sep 3.

Abstract

A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790M inhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858R kinase (IC50=3.3nM), but also was able to repress the replication of H1975 cells harboring EGFRT790M mutation at a concentration of 0.118μmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI=299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects.

Keywords: Azole-diphenylpyrimidine; EGFR T790M; Inhibitors; NSCLC; Synthesis.

MeSH terms

  • Azoles / chemical synthesis*
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azoles
  • Protein Kinase Inhibitors
  • Pyrimidines
  • EGFR protein, human
  • ErbB Receptors