Kinases have proven valuable targets in successful cancer drug discovery projects, but not yet for malignant brain tumors where type-II inhibition of cyclin-dependent kinase 5 (CDK5) stabilizing the DFG-out inactive state has potential for design of selective and clinically efficient drug candidates. In the absence of crystallographic evidence for a CDK5 DFG-out inactive state protein–ligand complex, for the first time, a model was designed using metadynamics/molecular dynamics simulations. Glide docking of the ZINC15 biogenic database identified [pyrimidin-2-yl]amino-furo[3,2-b]-furyl-urea/amide hit chemical scaffolds. For four selected analogues (4, 27, 36, and 42), potent effects on glioblastoma cell viability in U87-MG, T98G, and U251-MG cell lines and patient-derived cultures were generally observed (IC₅₀s ∼ 10–40 μM at 72 h). Selectivity profiling against 11 homologous kinases revealed multikinase inhibition (CDK2, CDK5, CDK9, and GSK-3α/β), most potent for GSK-3α in the nanomolar range (IC₅₀s ∼ 0.23–0.98 μM). These compounds may therefore have diverse anticancer mechanisms of action and are of considerable interest for lead optimization.

中文翻译：

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发现针对 DFG-out 非活性状态下的 CDK5 的有效多激酶 II 型抑制剂，具有抗胶质母细胞瘤的潜力

激酶在成功的癌症药物发现项目中已被证明是有价值的靶点，但尚未用于恶性脑肿瘤，其中细胞周期蛋白依赖性激酶 5 (CDK5) 的 II 型抑制稳定 DFG 失活状态，有可能设计出选择性和临床有效的药物候选人。在缺乏 CDK5 DFG 失活状态蛋白质-配体复合物的晶体学证据的情况下，首次使用元动力学/分子动力学模拟设计了模型。 ZINC15生物数据库的滑移对接鉴定出[嘧啶-2-基]氨基-呋喃[3,2- b ]-呋喃基-脲/酰胺命中化学支架。对于四种选定的类似物（4、27、36和42），通常观察到对 U87-MG、T98G 和 U251-MG 细胞系以及患者来源的培养物中胶质母细胞瘤细胞活力的有效影响（IC ₅₀ s ∼ 10–40 72 小时时 μM）。针对 11 种同源激酶的选择性分析揭示了多激酶抑制（CDK2、CDK5、CDK9 和 GSK-3α/β），其中对纳摩尔范围内的 GSK-3α 最有效（IC ₅₀ s ∼ 0.23–0.98 μM）。因此，这些化合物可能具有不同的抗癌作用机制，并且对于先导化合物的优化具有很大的意义。