dc.contributor.author | Dale, T | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Waalboer, D | |
dc.contributor.author | Adeniji-Popoola, O | |
dc.contributor.author | Ortiz-Ruiz, M-J | |
dc.contributor.author | Mallinger, A | |
dc.contributor.author | Samant, RS | |
dc.contributor.author | Czodrowski, P | |
dc.contributor.author | Musil, D | |
dc.contributor.author | Schwarz, D | |
dc.contributor.author | Schneider, K | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Ewan, K | |
dc.contributor.author | Fraser, E | |
dc.contributor.author | TePoele, R | |
dc.contributor.author | Court, W | |
dc.contributor.author | Box, G | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | de Haven Brandon, A | |
dc.contributor.author | Gowan, S | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Schneider, R | |
dc.contributor.author | Poeschke, O | |
dc.contributor.author | Blaukat, A | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Schiemann, K | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Wienke, D | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2016-10-26T16:05:21Z | |
dc.date.issued | 2015-12-01 | |
dc.identifier.citation | Nature chemical biology, 2015, 11 (12), pp. 973 - 980 | |
dc.identifier.issn | 1552-4450 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/187 | |
dc.identifier.eissn | 1552-4469 | |
dc.identifier.doi | 10.1038/nchembio.1952 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 973 - 980 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Colonic Neoplasms | |
dc.subject | Pyridines | |
dc.subject | Spiro Compounds | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Molecular Probes | |
dc.subject | Molecular Structure | |
dc.subject | Models, Molecular | |
dc.subject | Cyclin-Dependent Kinase 8 | |
dc.title | A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-10-01 | |
rioxxterms.versionofrecord | 10.1038/nchembio.1952 | |
rioxxterms.licenseref.startdate | 2015-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature chemical biology | |
pubs.issue | 12 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.publication-status | Published | |
pubs.volume | 11 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Tumour Biology & Metastasis | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Gowan, Sharon | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Eccles, Suzanne | |