Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
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DOI：
10.7554/elife.20722
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发表时间：
2016-12-09
期刊：
影响因子：
7.7
通讯作者：
Wienke, Dirk
中科院分区：
文献类型：
--
作者：
Clarke, Paul A.;Ortiz-Ruiz, Maria-Jesus;Wienke, Dirk
介体相关激酶CDK 8/19是肿瘤发生的背景依赖性驱动因子或抑制因子。预测其抑制具有多效性效应，但尚不清楚这是否会影响CDK 8/19抑制剂的临床效用。我们发现了两系列对CDK 8/19具有高选择性的有效化学探针。尽管药效学证据表明具有稳健的靶向活性，但这些化合物对人肿瘤细胞系和患者来源的异种移植物表现出适度但显著的功效。改变的基因表达与CDK 8/19抑制一致，包括与超级增强子、免疫和炎症反应以及干细胞功能相关的谱。在表达致癌β-连环蛋白的小鼠模型中，治疗将增生性肠隐窝内的细胞从干细胞转变为转运扩增表型。在两个物种中，在治疗相关暴露下，两种探针均不耐受。在两种结构差异化的化学系列中观察到的毒性的复杂性质与对CDK 8/19抑制剂的临床开发构成重大挑战的靶向效应一致。
Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.