A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
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Date
2015-12-01Author
Dale, T
Clarke, PA
Esdar, C
Waalboer, D
Adeniji-Popoola, O
Ortiz-Ruiz, M-J
Mallinger, A
Samant, RS
Czodrowski, P
Musil, D
Schwarz, D
Schneider, K
Stubbs, M
Ewan, K
Fraser, E
TePoele, R
Court, W
Box, G
Valenti, M
de Haven Brandon, A
Gowan, S
Rohdich, F
Raynaud, F
Schneider, R
Poeschke, O
Blaukat, A
Workman, P
Schiemann, K
Eccles, SA
Wienke, D
Blagg, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Humans
Colonic Neoplasms
Pyridines
Spiro Compounds
Cyclin-Dependent Kinases
Protein Kinase Inhibitors
Molecular Probes
Molecular Structure
Models, Molecular
Cyclin-Dependent Kinase 8
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis
Language
eng
Date accepted
2015-10-01
License start date
2015-12
Citation
Nature chemical biology, 2015, 11 (12), pp. 973 - 980
Publisher
NATURE PUBLISHING GROUP