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

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.
Haiqing Yu 1,  Yanxia Li 2,  Yang Ge 1,  Zhendong Song 1,  Changyuan Wang 1,  Shanshan Huang 1,  Yue Jin 1,  Xu Han 1,  Yuhong Zhen 1,  Kexin Liu 3,  Youwen Zhou 4,  Xiaodong Ma 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
  • 2 Respiratory Department, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
  • 3 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: kexinliu@dlmedu.edu.cn.
  • 4 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada. Electronic address: youwen.zhou@ubc.ca.
  • 5 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
PMID: 26829280 DOI: 10.1016/j.ejmech.2016.01.045
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.

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