5BNJ

CDK8/CYCC IN COMPLEX WITH 8-{3-Chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridin- 4-yl}-2,8-diaza-spiro[4.5]decan-1-one

Summary for 5BNJ

• Entry DOI: 10.2210/pdb5bnj/pdb
• Related: 4f7n
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, 8-{3-chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pyridin-4-yl}-2,8-diazaspiro[4.5]decan-1-one, ... (5 entities in total)
• Functional Keywords: cdk8 kinase / cyclin c, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P49336 P24863
• Total number of polymer chains: 2
• Total formula weight: 80984.73

Authors

Musil, D.,Blagg, J.,Wienke, D. (deposition date: 2015-05-26, release date: 2015-10-14, Last modification date: 2024-05-08)

Primary citation

Dale, T.,Clarke, P.A.,Esdar, C.,Waalboer, D.,Adeniji-Popoola, O.,Ortiz-Ruiz, M.J.,Mallinger, A.,Samant, R.S.,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, S.A.,Wienke, D.,Blagg, J.
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
Nat.Chem.Biol., 11:973-980, 2015

PubMed 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.

PubMed: 26502155
DOI: 10.1038/nchembio.1952

Experimental method

X-RAY DIFFRACTION (2.64 Å)