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dc.contributor.authorClarke, PAen_US
dc.contributor.authorOrtiz-Ruiz, M-Jen_US
dc.contributor.authorTePoele, Ren_US
dc.contributor.authorAdeniji-Popoola, Oen_US
dc.contributor.authorBox, Gen_US
dc.contributor.authorCourt, Wen_US
dc.contributor.authorCzasch, Sen_US
dc.contributor.authorEl Bawab, Sen_US
dc.contributor.authorEsdar, Cen_US
dc.contributor.authorEwan, Ken_US
dc.contributor.authorGowan, Sen_US
dc.contributor.authorDe Haven Brandon, Aen_US
dc.contributor.authorHewitt, Pen_US
dc.contributor.authorHobbs, SMen_US
dc.contributor.authorKaufmann, Wen_US
dc.contributor.authorMallinger, Aen_US
dc.contributor.authorRaynaud, Fen_US
dc.contributor.authorRoe, Ten_US
dc.contributor.authorRohdich, Fen_US
dc.contributor.authorSchiemann, Ken_US
dc.contributor.authorSimon, Sen_US
dc.contributor.authorSchneider, Ren_US
dc.contributor.authorValenti, Men_US
dc.contributor.authorWeigt, Sen_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorBlaukat, Aen_US
dc.contributor.authorDale, TCen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorHecht, Sen_US
dc.contributor.authorUrbahns, Ken_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorWienke, Den_US
dc.date.accessioned2019-01-25T09:50:38Z
dc.date.issued2016-12-09
dc.identifier.citationeLife, 2016, 5
dc.identifier.issn2050-084X
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3022
dc.identifier.eissn2050-084X
dc.identifier.doi10.7554/elife.20722
dc.description.abstractMediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.en_US
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectNeoplasmsen_US
dc.subjectDisease Models, Animalen_US
dc.subjectHyperplasiaen_US
dc.subjectCyclin-Dependent Kinasesen_US
dc.subjectAnti-Inflammatory Agentsen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectTreatment Outcomeen_US
dc.subjectCyclin-Dependent Kinase 8en_US
dc.subjectMediator Complexen_US
dc.subjectHeterograftsen_US
dc.titleAssessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.
dc.typeJournal Article
dcterms.dateAccepted2016-11-29
rioxxterms.versionofrecord10.7554/elife.20722
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-12-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfeLifeen_US
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/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume5en_US
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorWorkman, Paulen


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