Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold

  • Bioorg Med Chem. 2018 May 1;26(8):1810-1822. doi: 10.1016/j.bmc.2018.02.029.
Jinxing Hu  1 ,  Yufei Han  1 ,  Jingtao Wang  1 ,  Yue Liu  1 ,  Yanfang Zhao  1 ,  Yajing Liu  2 ,  Ping Gong  3
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: [email protected].
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 29486953 DOI: 10.1016/j.bmc.2018.02.029
Abstract

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung Cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and K-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.

Keywords
L858R/T790M double mutants; N-9-Diphenyl-9H-purin-2-amine derivatives; Non-small cell lung cancer.