Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants

  • Eur J Med Chem. 2017 Jul 28:135:12-23. doi: 10.1016/j.ejmech.2017.04.036.
Haoyang Zhang  1 ,  Wenkui Wu  1 ,  Chao Feng  2 ,  Zhaogang Liu  2 ,  Enhe Bai  3 ,  Xueyuan Wang  1 ,  Meng Lei  3 ,  Hao Cheng  2 ,  Huayun Feng  3 ,  Jingmiao Shi  2 ,  Jia Wang  2 ,  Zhao Zhang  1 ,  Tao Jin  1 ,  Shanshan Chen  2 ,  Shihe Hu  4 ,  Yongqiang Zhu  5
Affiliations
  • 1. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
  • 2. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China.
  • 3. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
  • 4. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China. Electronic address: [email protected].
  • 5. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China. Electronic address: [email protected].
PMID: 28426996 DOI: 10.1016/j.ejmech.2017.04.036
Abstract

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung Cancer (NSCLC) cells bearing T790M/L858R and in vivo Anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.

Keywords
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives; EGFR modulator; L858R/T790M double mutants; Non-small cell lung cancer.