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

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

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: hsh.2@163.com.
  • 5 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China. Electronic address: zhyqscu@hotmail.com.
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.

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