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Nat Chem Biol. 2015 Dec;11(12):973-980. doi: 10.1038/nchembio.1952. Epub 2015 Oct 26.

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

Author information

1
School of Bioscience, Cardiff University, Cardiff, UK.
2
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP.
3
Merck KGaA, Merck Serono, Darmstadt, Germany.
#
Contributed equally

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.

PMID:
26502155
PMCID:
PMC4677459
DOI:
10.1038/nchembio.1952
[Indexed for MEDLINE]
Free PMC Article

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