2. Academic Validation
  3. Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant

Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant

  • Eur J Med Chem. 2015 Nov 2:104:115-26. doi: 10.1016/j.ejmech.2015.09.031.
Mingze Qin 1,  Tingting Wang 1,  Boxuan Xu 1,  Zonghui Ma 1,  Nan Jiang 1,  Hongbo Xie 2,  Ping Gong 3,  Yanfang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: yanfangzhao@126.com.
PMID: 26451770 DOI: 10.1016/j.ejmech.2015.09.031
Abstract

The epidermal growth factor receptor (EGFR) T790M mutant is found in approximately 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung Cancer (NSCLC). Here, a series of novel aminopyrimidines bearing a hydrazone moiety were identified as potent and selective EGFR inhibitors. Compounds 14a, 15g, and 15i potently inhibited all EGFR mutants including EGFR T790M/L858R, EGFR T790M/delE746_A750, and EGFR T790M while they showed weak effects on the wild type (WT) EGFR. In addition, these compounds effectively suppressed proliferation of gefitinib-resistant H1975 (EGFR T790M/L858R) cells but were less potent against A549 (WT EGFR and K-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. Therefore, 14a, 15g, and 15i might be promising candidates to overcome drug resistance mediated by the EGFR T790M mutant.

Keywords

Aminopyrimidines; Antitumor activity; EGFR T790M mutant; Synthesis.

Figures