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
语种：
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.
