Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors

  • Bioorg Med Chem. 2016 Nov 1;24(21):5505-5512. doi: 10.1016/j.bmc.2016.09.001.
Zhendong Song  1 ,  Yue Jin  1 ,  Yang Ge  1 ,  Changyuan Wang  1 ,  Jianbin Zhang  1 ,  Zeyao Tang  1 ,  Jinyong Peng  1 ,  Kexin Liu  1 ,  Yanxia Li  2 ,  Xiaodong Ma  3
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. Electronic address: [email protected].
  • 3. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: [email protected].
PMID: 27634676 DOI: 10.1016/j.bmc.2016.09.001
Abstract

A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790M inhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858R kinase (IC50=3.3nM), but also was able to repress the replication of H1975 cells harboring EGFRT790M mutation at a concentration of 0.118μmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI=299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects.

Keywords
Azole-diphenylpyrimidine; EGFR T790M; Inhibitors; NSCLC; Synthesis.