A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics.
A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics.
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DOI：
10.1021/acs.jmedchem.1c01951
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发表时间：
2022-02
影响因子：
7.3
通讯作者：
Li Zhang;Chen Cheng;Jing Li;Lili Wang;A. Chumanevich;Donald C. Porter;Aleksei Mindich;S. Gorbunova;I. Roninson;Mengqian Chen;Campbell McInnes
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文献类型：
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作者：
Li Zhang;Chen Cheng;Jing Li;Lili Wang;A. Chumanevich;Donald C. Porter;Aleksei Mindich;S. Gorbunova;I. Roninson;Mengqian Chen;Campbell McInnes
Senexins是CDK8/19介体激酶的强效和选择性的喹唑啉抑制剂。为了提高喹啉类化合物的药效和代谢稳定性，在模拟药物靶向对接模型的基础上，通过结构导向策略设计了喹啉类化合物。合成了喹啉类化合物的构效关系文库。优化后的化合物20a(Senexin C)具有较强的CDK8/19抑制活性，且选择性较高。与原型抑制剂Senexin B相比，Senexin C在代谢上更稳定，对依赖CDK8/19的细胞基因表达的抑制更持久。采用一种新的基于肿瘤的PD分析方法进行体内药代动力学(PK)和药效学(PD)评估表明，Senexin C具有良好的口服生物利用度，具有很强的肿瘤浓缩PK谱和肿瘤-PD标记反应。在耐受性良好的系统体内模型中，Senexin C抑制MV4-11白血病的生长。
Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug-target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure-activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.