ArticleeLife2016
Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
49 citing papers in PubMed.
- Inhibition of cyclin-dependent kinase 8 modulates chondrocyte transition to hypertrophy and provides in vivo protection against spontaneous osteoarthritis.Bone research · 2026Article
- A novel CDK8/19 inhibitor RO8323 mitigates allograft rejection through dual mechanisms of action to modulate regulatory T cell and myeloid cell.Acta pharmacologica Sinica · 2026Article
- The Mediator Complex: From Transcriptional Regulation to Disease Pathogenesis.International journal of molecular sciences · 2026Review
- Mediator Kinase Inhibitor Selectivity and Activity in Colorectal Cancer.ACS chemical biology · 2025Article
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- Article
- Super-enhancers in tumors: unraveling recent advances in their role in Oncogenesis and the emergence of targeted therapies.Journal of translational medicine · 2025Review
- Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.Signal transduction and targeted therapy · 2025Review
- Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.The Journal of clinical investigation · 2024Article
- Unveiling the impact of CDK8 on tumor progression: mechanisms and therapeutic strategies.Frontiers in pharmacology · 2024Review
- Targeting super-enhancer activity for colorectal cancer therapy.American journal of translational research · 2024Review
- Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex.International journal of molecular sciences · 2023Review
- Emerging approaches to CDK inhibitor development, a structural perspective.RSC chemical biology · 2023Article
- CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium.EMBO reports · 2023Article
- The era of high-quality chemical probes.RSC medicinal chemistry · 2022Article
- MK256 is a novel CDK8 inhibitor with potent antitumor activity in AML through downregulation of the STAT pathway.Oncotarget · 2022Article
- CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF.The Journal of clinical investigation · 2022Article
- Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer.Oncogene · 2022Review
- Targeting transcription cycles in cancer.Nature reviews. Cancer · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
32 authors.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.