期刊
NATURE CHEMICAL BIOLOGY
卷 11, 期 12, 页码 973-980出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1952
关键词
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资金
- Cancer Research UK [C309/A11566, C368/A6743, A368/A7990]
- Cancer Research UK
- Royal Marsden National Health Service (NHS)
- BBSRC [BB/G016887/1]
- BBSRC [BB/D00117X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D00117X/1] Funding Source: researchfish
- Cancer Research UK [11566, 15937] Funding Source: researchfish
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.
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