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|Public on Oct 26, 2015
|Identification of a potent and selective chemical probe for exploring the role of Mediator complex-associated protein kinases CDK8 and CDK19 in human disease [Colo205]
|Expression profiling by array
|There is an 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 WNT-pathway inhibitor discovered by cell-based screening
is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19
CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression
but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally
we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours.
|Colo205 colon cancer cells were treated with 350 nM of Compound 1 or with vehicle (DMSO) for 2 or 6h. Four samples with four biological repeats each. Samples were hybridized against human reference.
Compound 1 is a close analogue of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. It was shown to be potent and selective inhibitor of the Mediator complex-associated protein kinases CDK8 and CDK19. Its is ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.
|Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz M, Mallinger A, Samant R, Czodrowski P, Musil D, Schwarz D, Schneider K, Schneider EV, Lammens A, Stubbs M, Ewan K, Fraser E, te Poele RH, 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
|Apr 14, 2015
|Last update date
|Jan 09, 2018
|Robert te Poele
|The Institute of Cancer Research
|Cancer Reserach UK Unit for Cancer Therapeutics
|Signal Transduction and Molecular Pharmacology Team
|15 Cotswold Road
|Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)
|This SubSeries is part of SuperSeries:
|Identification of a potent and selective chemical probe for exploring the role of Mediator complex-associated protein kinases CDK8 and CDK19 in human disease
|TAR (of TXT)