Novel 4-anilinoquinazoline derivatives featuring an 1-adamantyl moiety as potent EGFR inhibitors with enhanced activity against NSCLC cell lines

Eur J Med Chem. 2016 Mar 3:110:195-203. doi: 10.1016/j.ejmech.2016.01.045. Epub 2016 Jan 26.

Abstract

With the aim of overcoming gefitinib resistance, a series of novel quinazoline derivatives bearing an adamantyl group on the aniline ring were synthesized as potent epidermal growth factor receptor (EGFR) inhibitors. Most of these analogues are comparable to gefitinib in their ability to inhibit non-small cell lung cancer (NSCLC) cell lines, and several also exhibited significantly enhanced anti-tumor potency. Specifically, compound 3d, with an IC50 value of 2.06 μM against A431 cells with the wild-type EGFR and of 0.009 μM against the gefitinib-sensitive cells, displayed approximately 5-fold higher potency than the lead compound to inhibit the cells harboring the EGFR(T790M) mutant. In addition, the molecular simulation and Western blot analysis results also indicated that these compounds effectively interfered with the EGFR(T790M) activity, and may serve as a new alternative structure to develop more effective antitumor agents.

Keywords: Adamantyl; EGFR; NSCLC; Quinazoline; T790M.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gefitinib
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Molecular Docking Simulation
  • Point Mutation
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Quinazolines
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib