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

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ICR Authors

Clarke, Paul
 Gowan, Sharon
 Raynaud, Florence
 Workman, Paul
 Eccles, Suzanne

Authors

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

Document Type

Journal Article

Date

2015-12-01

Date Accepted

2015-10-01

Abstract

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.

Citation

Nature chemical biology, 2015, 11 (12), pp. 973 - 980

DOI

10.1038/nchembio.1952

URI

https://repository.icr.ac.uk/handle/internal/187

Rights

Source Title

Publisher

NATURE PUBLISHING GROUP

ISSN

1552-4450

eISSN

1552-4469

Collections

Cancer Therapeutics

Research Team

Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis

Notes