A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease
| Autor: | Alexis De Haven Brandon, Paul Workman, Aurélie Mallinger, Elizabeth Fraser, Mark Stubbs, Paul Czodrowski, Andree Blaukat, Richard Schneider, Julian Blagg, Djordje Musil, Melanie Valenti, Daniel Schwarz, Rahul S. Samant, Klaus Schneider, Kai Schiemann, Sharon Gowan, Christina Esdar, Florence I. Raynaud, Suzanne A. Eccles, Robert TePoele, Dennis Waalboer, Gary Box, Dirk Wienke, Oliver Poeschke, Paul A. Clarke, Maria-Jesus Ortiz-Ruiz, Kenneth Burnside Ramsay Ewan, Trevor Clive Dale, Felix Rohdich, Olajumoke Adeniji-Popoola, Will Court |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Pyridines Article Mediator Cyclin-dependent kinase In vivo Cell Line Tumor Humans Spiro Compounds Kinase activity Protein Kinase Inhibitors Molecular Biology Molecular Structure biology Kinase Wnt signaling pathway Cell Biology Cyclin-Dependent Kinase 8 Cyclin-Dependent Kinases Cell biology Biochemistry Molecular Probes Colonic Neoplasms biology.protein Cyclin-dependent kinase 8 Phosphorylation |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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 STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors. |
| Databáze: | OpenAIRE |
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