European Journal of Medicinal Chemistry p. 12 - 23 (2017)
Update date:2022-08-26
Topics:
Zhang, Haoyang
Wu, Wenkui
Feng, Chao
Liu, Zhaogang
Bai, Enhe
Wang, Xueyuan
Lei, Meng
Cheng, Hao
Feng, Huayun
Shi, Jingmiao
Wang, Jia
Zhang, Zhao
Jin, Tao
Chen, Shanshan
Hu, Shihe
Zhu, Yongqiang
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.
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