文章基本信息

标题：Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors
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作者：Yuanbiao Tu ; Caolin Wang ; Zunhua Yang 等
期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2018
卷号：16
页码：462-478
DOI：10.1016/j.csbj.2018.10.016
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出版社：Computational and Structural Biotechnology Journal
摘要：Aimed at discovering effective EGFR inhibitors, six series of quinazoline derivatives bearing a semicarbazone moiety were designed, synthesized and evaluated in different cancer cell lines (A549, HepG2, MCF-7 and PC-3). Most of the selected compounds showed remarkable cytotoxicity with IC₅₀ values reaching the nanomole range. Further, the inhibition efficacy of 11 compounds against EGFR kinases was tested, which demonstrated excellent IC₅₀ values in nanomolar level. Importantly, 2 compounds exhibited IC₅₀ values of 0.05 nM and 0.1 nM against wild type EGFR respectively, suggesting more potent activities than that of the positive control, Afatinib (4.0 nM). Excitingly, 2 compounds showed excellent enzyme inhibitory activity with 8.6 nM and 5.6 nM for double T790 M/L858R mutant EGFRs, which is almost the same as Afatinib (3.8 nM). Structure–activity relationships (SARs) analysis indicated that the type of small molecule amine in pyrrole moiety or the chain length of pyrrolamine moiety had no obvious impact on the inhibition efficacy of our synthesized compounds against cancer cells. In addition, results of cell cycle analysis indicated that the G2/M phase of A549 cells was efficiently arrested by the selected compounds. These preliminary results demonstrate that 2 compounds may be promising lead compound-targeting EGFR.
关键词：Quinazoline ; Semicarbazone moiety ; EGFR kinase inhibitors ; Anti-tumor activity ; Docking study