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

被引：117

作者：

Dale, Trevor ^{[1
]}

Clarke, Paul A. ^{[2
]}

Esdar, Christina ^{[3
]}

Waalboer, Dennis ^{[2
]}

Adeniji-Popoola, Olajumoke ^{[2
]}

Ortiz-Ruiz, Maria-Jesus ^{[2
]}

Mallinger, Aurelie ^{[2
]}

Samant, Rahul S. ^{[2
]}

Czodrowski, Paul ^{[3
]}

Musil, Djordje ^{[3
]}

Schwarz, Daniel ^{[3
]}

Schneider, Klaus ^{[3
]}

Stubbs, Mark ^{[2
]}

Ewan, Ken ^{[1
]}

Fraser, Elizabeth ^{[1
]}

TePoele, Robert ^{[2
]}

Court, Will ^{[2
]}

Box, Gary ^{[2
]}

Valenti, Melanie ^{[2
]}

Brandon, Alexis de Haven ^{[2
]}

Gowan, Sharon ^{[2
]}

Rohdich, Felix ^{[3
]}

Raynaud, Florence ^{[2
]}

Schneider, Richard ^{[3
]}

Poeschke, Oliver ^{[3
]}

Blaukat, Andree ^{[3
]}

Workman, Paul ^{[2
]}

Schiemann, Kai ^{[3
]}

Eccles, Suzanne A. ^{[2
]}

Wienke, Dirk ^{[3
]}

Blagg, Julian ^{[2
]}

机构：

[1] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales

[2] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW3 6JB, England

[3] Merck Serono, Merck KGaA, Darmstadt, Germany

来源：

NATURE CHEMICAL BIOLOGY | 2015年 / 11卷 / 12期

基金：

英国生物技术与生命科学研究理事会;

关键词：

TYROSINE KINASE INHIBITOR; BETA-CATENIN; MEDIATOR COMPLEX; POSITIVE REGULATOR; TARGET; TRANSCRIPTION; CANCER; PROGRESSION; ELONGATION; ACTIVATION;

D O I：

10.1038/nchembio.1952

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：973 / 980

页数：8

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