Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4832-4837. doi: 10.1016/j.bmcl.2017.09.048. Epub 2017 Sep 25.

Abstract

A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 - 750) or Z'LYTE assay method (EGFR-WT, EGFR d746 - 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho-hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10µM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9-12 exhibited complete inhibition at 10µM and nearly complete inhibition at 1µM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7, 9-12, 30 and 31 were found to be the most potent compounds across all five cell lines.

Keywords: Anilinopyrimidine; EGFR; EGFR triple mutant; NSCLC; TKIs; WZ4002.

MeSH terms

  • Acrylamides / chemistry*
  • Acrylamides / metabolism
  • Acrylamides / toxicity
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Mice
  • Mutagenesis, Site-Directed
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / toxicity
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / toxicity
  • Structure-Activity Relationship

Substances

  • Acrylamides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • WZ4002
  • ErbB Receptors
  • pyrimidine