Novel morpholin-3-one fused quinazoline derivatives as EGFR tyrosine kinase inhibitors

Bioorg Med Chem Lett. 2016 Mar 15;26(6):1571-1575. doi: 10.1016/j.bmcl.2016.02.009. Epub 2016 Feb 4.

Abstract

A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFR(wt) kinase (IC50<1 μM). Compound a8 demonstrated the most potent inhibitory activity toward EGFR(wt) (IC50=53.1 nM). Compound a7 and a8 showed excellent inhibitory activities against mutant EGFR(T790M/L858R) and strong antiproliferative activity against H358 and A549 cell lines. Finally, molecular docking studies were performed to predict the possible binding mode of the target compounds. It is believed that this work would be very useful for designing a new series of tyrosine kinase inhibitors targeting EGFR.

Keywords: Anti-cancer; EGFR inhibitors; Molecular docking; NSCLC; Quinazoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Morpholines
  • Protein Kinase Inhibitors
  • Quinazolines
  • ErbB Receptors