Hao Chenzhou, Huang Wanxu, Li Xiaodong, Guo Jing, Chen Meng, Yan Zizheng, Wang Kai, Jiang Xiaolin, Song Shuai, Wang Jian, Zhao Dongmei, Li Feng, Cheng Maosheng
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Eur J Med Chem. 2017 May 5;131:1-13. doi: 10.1016/j.ejmech.2017.02.063. Epub 2017 Mar 8.
Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC = 0.790 μM) 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 IC = 0.033 μM). 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.
在分析已报道的PAK4抑制剂KY04031（PAK4 IC = 0.790 μM）在PAK4活性位点的晶体结构后，我们研究了将KY04031的三嗪核心替换为喹唑啉的可能性。以KY04031为起始化合物，设计并合成了一系列2,4-二氨基喹唑啉衍生物。对这些化合物进行了PAK4抑制活性评估，从而鉴定出化合物9d（PAK4 IC = 0.033 μM）。化合物9d显著诱导细胞周期进入G1/S期，并通过调节PAK4-LIMK1信号通路抑制过表达PAK4的A549细胞的迁移和侵袭。对化合物9d进行了对接研究，以阐明其可能的结合模式，并为PAK4抑制剂的进一步结构导向设计提供结构基础。化合物9d可作为抗癌药物发现的先导化合物，以及用于PAK4进一步生物学研究的有价值的研究探针。
