ArticleCells2019
Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition.
Article in Cells, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 57 citations in OpenAlex.
- 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
- Autophagic Pathway on GABARAP Involved in GABANeurochemical research · 2026Review
- The Mediator Complex: From Transcriptional Regulation to Disease Pathogenesis.International journal of molecular sciences · 2026Review
- Anoikis resistance and metastasis of ovarian cancer can be overcome by CDK8/19 mediator kinase inhibition.JCI insight · 2026Article
- Inhibition of CDK8 rescues impaired ischemic fracture healing.NPJ Regenerative medicine · 2026Article
- Selective Dual Inhibition of TNKS1 and CDK8 by TCS9725 Attenuates STAT1/β-Catenin/TGFβ1 Signaling in Renal Cancer.Current issues in molecular biology · 2025Article
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- CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells.Cell death discovery · 2025Article
- The Cyclin-Dependent Kinase 8 Inhibitor E966-0530-45418 Attenuates Pulmonary FibrosisInternational journal of biological sciences · 2025Article
- Mediator kinase inhibitors suppress triple-negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies.Pharmaceutics · 2024Article
- Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.The Journal of clinical investigation · 2024Article
- CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells.Journal of virology · 2023Article
- CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.Nucleic acids research · 2023Article
- Inhibition of Cyclin-Dependent Kinases 8/19 Restricts Bacterial and Virus-Induced Inflammatory Responses in Monocytes.Viruses · 2023Article
- Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex.International journal of molecular sciences · 2023Review
- CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium.EMBO reports · 2023Article
- Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors.Cancer research · 2023Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 inhibition, Cmpd3, Cmpd4, dCA and 15w showed similar low-nanomolar potency and efficacy against CDK8 and CDK19, while Senexin B was less potent. Only dCA produced sustained inhibition of CDK8/19-dependent gene expression. While toxicity of different compounds did not correlate with their effects on CDK8 and CDK19, kinome profiling identified several off-target kinases for both Cmpd3 and Cmpd4, which could be responsible for their toxicity. Off-target activities could have been achieved in the study of Clarke et al. due to high in vivo doses of Cmpd3 and Cmpd4, chosen for the ability to inhibit STAT1 S727 phosphorylation in tumor xenografts. We show here that STAT1 S727 phosphorylation is induced by various cytokines and stress stimuli in CDK8/19-independent manner, indicating that it is not a reliable pharmacodynamic marker of CDK8/19 activity. These results illustrate the need for careful off-target analysis and dose selection in the 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.