4.8 Article

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

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ELIFE
卷 5, 期 -, 页码 -

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ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.20722

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  1. Breast Cancer Now [2008MayPR16]
  2. Cancer Research UK [C309/A11566, C368/A6743, A368/A7990]
  3. Cancer Research UK [11566] Funding Source: researchfish

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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.

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