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A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Dale, Trevor ORCID:, Clarke, Paul A., Esdar, Christina, Waalboer, Dennis, Adeniji-Popoola, Olajumoke, Ortiz-Ruiz, Maria-Jesus, Mallinger, Aurélie, Samant, Rahul S., Czodrowski, Paul, Musil, Djordje, Schwarz, Daniel, Schneider, Klaus, Stubbs, Mark, Ewan, Ken ORCID:, Fraser, Elizabeth, TePoele, Robert, Court, Will, Box, Gary, Valenti, Melanie, de Haven Brandon, Alexis, Gowan, Sharon, Rohdich, Felix, Raynaud, Florence, Schneider, Richard, Poeschke, Oliver, Blaukat, Andree, Workman, Paul, Schiemann, Kai, Eccles, Suzanne A., Wienke, Dirk and Blagg, Julian 2015. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nature Chemical Biology 11 , pp. 973-980. 10.1038/nchembio.1952

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There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex–associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway–regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
Publisher: Nature Research
ISSN: 1552-4450
Date of Acceptance: 1 October 2015
Last Modified: 22 Jun 2023 10:00

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