The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

  • Bioorg Med Chem. 2018 Dec 15;26(23-24):6087-6095. doi: 10.1016/j.bmc.2018.11.009.
Lixue Chen  1 ,  Fuyun Chi  2 ,  Tong Wang  1 ,  Ning Wang  2 ,  Wei Li  1 ,  Kexin Liu  2 ,  Xiaohong Shu  2 ,  Xiaodong Ma  3 ,  Youjun Xu  4
Affiliations
  • 1. School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
  • 3. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: [email protected].
  • 4. School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 30471829 DOI: 10.1016/j.bmc.2018.11.009
Abstract

A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFRT790M/L858R inhibitors among which 9c (IC50 = 0.5872 nM), 9d (IC50 = 2.213 nM), or 9h (IC50 = 12.57 nM) showed more potent anti-EGFRT790M/L858R activity compared with AZD-9291 (IC50 = 20.80 nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFRT790M/L858R over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC50 of 1.664 μM and exhibited low toxicity against the normal HBE cells (IC50 > 20 μΜ). 9h had moderate selectivity for H 1975 over A 431 (SI = 7.0) and the Other selected cell lines. Morphological staining results further indicated that 9h could promote Apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFRT790M/L858R inhibitor for the treatment of NSCLC.

Keywords
EGFR T790M/L858R; Inhibitors; NSCLC; Resistance.