Discovery of new thieno[3,2-d]pyrimidine derivatives targeting EGFRL858R/T790M NSCLCs by the conformation constrained strategy

被引:15
作者
Chen, Yang [1 ]
Yang, Linlin [2 ]
Qiao, Hui [1 ]
Cheng, Zhongyu [1 ]
Xie, Jiahao [1 ]
Zhou, Wenjuan [1 ]
Huang, Xin [1 ]
Jiang, Yaoxuan [1 ]
Yu, Bin [1 ]
Zhao, Wen [1 ]
机构
[1] Zhengzhou Univ, Key Lab Adv Pharmaceut Technol, State Key Lab Esophageal Canc Prevent & Treatment, Sch Pharmaceut Sci,Minist Educ China, Zhengzhou 450001, Henan, Peoples R China
[2] Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, Zhengzhou 450001, Peoples R China
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
Thieno[3,2-d]pyrimidine; Quinolin-2(1H)-Ones; EGFR inhibitors; Lung cancer; CELL LUNG-CANCER; EGFR; RECEPTOR; RESISTANCE; INHIBITORS; ACTIVATION; MECHANISMS; ERLOTINIB; MUTANTS;
D O I
10.1016/j.ejmech.2020.112388
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Studies on the third-generation of epidermal growth factor receptor tyrosine kinase inhibitors (EGERTKIs) targeting EGFR(L858R/T790M) mutant remain hotspots, specifically for non-small cell lung cancer (NSCLC). In the current study, a new series of EGFR-TKIs with thieno[3,2-d]pyrimidine derivatives(6a-6r) bearing quinolin-2(1H)-ones were designed and synthesized, through conformational constrained strategy from the third generation of EGFR-TKI olmutinib. In vitro structure-activity relationship (SAR) studies indicated that compounds 6a, 6l, 6m, 6n and 6o exhibited good selective inhibition to EGFR(L858R/T790M) (IC50 <= 250 nM) over wild type EGFR (IC50 > 10000 nM). The observed selectivity of compounds 6l and 6o was also proved by the computational molecular docking and the cellular thermal shift assay. These compounds had good growth inhibitory effect on the four tested cancer cell lines. Specifically, 6o could significantly inhibit the colony formation, wound healing and the expression of p-EGFR and its downstream p-ERK in EGFR(L858R/T790M) lung cancer cells. Our findings suggest that the thieno[3,2d]pyrimidine compounds, especially 6l and 6o, can selectively target the mutant EGFR(L858R/T790M) in vitro and at cellular level and may serve as the lead compounds for generating new series of the third-generation EGFR-TKIs. (C) 2020 Published by Elsevier Masson SAS.
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页数:13
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