Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy
Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy
复制标题
通过核心精细化策略开发2, 4-二氨基喹唑啉衍生物作为有效的PAK4抑制剂
DOI：
10.1016/j.ejmech.2017.02.063
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发表时间：
2017-05-05
影响因子：
6.7
通讯作者：
Cheng, Maosheng
中科院分区：
文献类型：
--
作者：
Hao, Chenzhou;Huang, Wanxu;Cheng, Maosheng
通过分析PAK4抑制剂KY04031 （PAK4 IC50 = 0.790 μ M）在PAK4活性位点的晶体结构，我们探讨了将KY04031的三嗪核心改为喹唑啉的可能性。以KY04031为起始化合物，设计并合成了2,4 -二氨基喹唑啉衍生物库。对这些化合物进行PAK4抑制评价，鉴定出化合物9d （PAK4 IC50 = 0.033 μ M）。化合物9d通过调控PAK4- limk1信号通路，显著诱导细胞周期进入G1/S期，抑制过表达PAK4的A549细胞的迁移和侵袭。对化合物9d进行对接研究，阐明其可能的结合模式，并为进一步以结构为导向设计PAK4抑制剂提供结构基础。化合物9d可作为抗癌药物开发的先导化合物，也可作为PAK4进一步生物学研究的重要探针。(C) 2017年由Elsevier Masson SAS出版。
Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 mu M) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 mu M). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4. (C) 2017 Published by Elsevier Masson SAS.