Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University , Shenyang 110016, China.
Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University , Beijing 100084, China.
J Med Chem. 2018 Jan 11;61(1):265-285. doi: 10.1021/acs.jmedchem.7b01342. Epub 2017 Dec 30.
Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.
在此，我们报告了一类新型的以喹唑啉为骨架的 PAK4 抑制剂的发现和特征。基于 PAKs 的 ATP 结合口袋的形状和化学成分，我们选择了 2,4-二氨基喹唑啉系列抑制剂作为起点。通过 X 射线晶体学和基于结构的药物设计（SBDD）方法的指导，设计并合成了一系列新型的 4-氨基喹唑啉-2-甲酰胺 PAK4 抑制剂。对抑制剂的选择性、治疗效力和药物性质进行了优化。其中一种最佳化合物 31（CZh226）表现出显著的 PAK4 选择性（对 PAK1 的选择性为 346 倍）和良好的激酶选择性特征。此外，该化合物通过调节体外 PAK4 靶向的下游信号通路，强烈抑制 A549 肿瘤细胞的迁移和侵袭。综上所述，这些数据支持进一步开发 31 作为针对 PAK4 的抗癌药物发现的先导化合物，并作为进一步研究 II 组 PAK 的有价值的研究探针。
