Synthesis and biological evaluation of morpholine-substituted diphenylpyrimidine derivatives (Mor-DPPYs) as potent EGFR T790M inhibitors with improved activity toward the gefitinib-resistant non-small cell lung cancers (NSCLC)

  • Eur J Med Chem. 2017 Jun 16:133:329-339. doi: 10.1016/j.ejmech.2017.03.083.
Zhendong Song  1 ,  Shanshan Huang  1 ,  Haiqing Yu  1 ,  Yu Jiang  1 ,  Changyuan Wang  1 ,  Qiang Meng  1 ,  Xiaohong Shu  1 ,  Hunjun Sun  1 ,  Kexin Liu  1 ,  Yanxia Li  2 ,  Xiaodong Ma  3
Affiliations
  • 1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
  • 2. Department of Respiratory Medicine, 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: [email protected].
PMID: 28395219 DOI: 10.1016/j.ejmech.2017.03.083
Abstract

Potential new EGFRT790M inhibitors comprised of structurally modified diphenylpyrimidine derivatives bearing a morpholine functionality (Mor-DPPYs) were used to improve the activity and selectivity of gefitinib-resistant non-small cell lung Cancer (NSCLC) treatment. This led to the identification of inhibitor 10c, which displayed high activity against EGFRT790M/L858R kinase (IC50 = 0.71 nM) and repressed H1975 cell replication harboring EGFRT790M mutations at a concentration of 0.037 μM. Inhibitor 10c demonstrated high selectivity (SI = 631.9) for T790M-containing EGFR mutants over wild type EGFR, suggesting that it will cause less side effects. Moreover, this compound also shows promising antitumor efficacy in a murine EGFRT790M/L858R-driven H1975 xenograft model without affecting body weight. This study provides new potential lead compounds for further development of anti-NSCLC drugs.

Keywords
EGFR T790M; Inhibitors; NSCLC; Pyrimidine; Resistance.