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dc.contributor.authorDale, T
dc.contributor.authorClarke, PA
dc.contributor.authorEsdar, C
dc.contributor.authorWaalboer, D
dc.contributor.authorAdeniji-Popoola, O
dc.contributor.authorOrtiz-Ruiz, M-J
dc.contributor.authorMallinger, A
dc.contributor.authorSamant, RS
dc.contributor.authorCzodrowski, P
dc.contributor.authorMusil, D
dc.contributor.authorSchwarz, D
dc.contributor.authorSchneider, K
dc.contributor.authorStubbs, M
dc.contributor.authorEwan, K
dc.contributor.authorFraser, E
dc.contributor.authorTePoele, R
dc.contributor.authorCourt, W
dc.contributor.authorBox, G
dc.contributor.authorValenti, M
dc.contributor.authorde Haven Brandon, A
dc.contributor.authorGowan, S
dc.contributor.authorRohdich, F
dc.contributor.authorRaynaud, F
dc.contributor.authorSchneider, R
dc.contributor.authorPoeschke, O
dc.contributor.authorBlaukat, A
dc.contributor.authorWorkman, P
dc.contributor.authorSchiemann, K
dc.contributor.authorEccles, SA
dc.contributor.authorWienke, D
dc.contributor.authorBlagg, J
dc.date.accessioned2016-10-26T16:05:21Z
dc.date.issued2015-12
dc.identifier.citationNature chemical biology, 2015, 11 (12), pp. 973 - 980
dc.identifier.issn1552-4450
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/187
dc.identifier.eissn1552-4469
dc.identifier.doi10.1038/nchembio.1952
dc.description.abstractThere 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.formatPrint-Electronic
dc.format.extent973 - 980
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectColonic Neoplasms
dc.subjectPyridines
dc.subjectSpiro Compounds
dc.subjectCyclin-Dependent Kinases
dc.subjectProtein Kinase Inhibitors
dc.subjectMolecular Probes
dc.subjectMolecular Structure
dc.subjectModels, Molecular
dc.subjectCyclin-Dependent Kinase 8
dc.titleA selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
dc.typeJournal Article
dcterms.dateAccepted2015-10-01
rioxxterms.versionofrecord10.1038/nchembio.1952
rioxxterms.licenseref.startdate2015-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature chemical biology
pubs.issue12
pubs.notesNo 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-statusPublished
pubs.volume11
pubs.embargo.termsNo embargo
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamTumour Biology & Metastasisen_US
dc.contributor.icrauthorEccles, Suzanneen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorSamant, Rahulen
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorWorkman, Paulen


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