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外文期刊>Journal of Medicinal Chemistry
>A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
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A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
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.
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机译:Senexins 是 CDK8/19 介导激酶的有效选择性喹唑啉抑制剂。为提高喹啉基衍生物的效力和代谢稳定性,基于千内辛A和千内辛B的模拟药物-靶点对接模型,采用结构引导策略设计了喹啉基衍生物。合成喹啉-千里光素衍生物库,探究其构效关系(SAR)。优化的化合物 20a (Senexin C) 具有有效的 CDK8/19 抑制活性和高选择性。与原型抑制剂 Senexin B 相比,Senexin C 的代谢更稳定,并且对 CDK8/19 依赖性细胞基因表达具有更持久的抑制作用。使用新型基于肿瘤的 PD 测定进行体内药代动力学 (PK) 和药效学 (PD) 评估显示,Senexin C 具有良好的口服生物利用度,具有很强的肿瘤富集 PK 谱和肿瘤-PD 标志物反应。Senexin C 在全身体内模型中抑制 MV4-11 白血病生长,具有良好的耐受性。
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