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.

中文翻译：

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基于结构的6-氯-4-氨基喹唑啉-2-羧酰胺衍生物作为有效和选择性p21活化激酶4（PAK4）抑制剂的设计。

在本文中，我们报告了喹唑啉支架新型PAK4抑制剂的发现和表征。根据PAKs ATP结合袋的形状和化学组成，我们选择了2,4-二氨基喹唑啉系列抑制剂作为起始点。在X射线晶体学和基于结构的药物设计（SBDD）方法的指导下，设计和合成了一系列新型的4-氨基喹唑啉-2-羧酰胺PAK4抑制剂。优化了抑制剂的选择性，治疗效果和药物特性。最好的化合物之一31（CZh226），表现出显着的PAK4选择性（是PAK1的346倍）和有利的激酶选择性谱。此外，该化合物通过在体外调节PAK4定向的下游信号通路有效抑制A549肿瘤细胞的迁移和侵袭。综上所述，这些数据支持31作为PAK4靶向抗癌药物发现的先导化合物和II类PAK进一步生物学研究的有价值的研究探针的进一步开发。