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dc.contributor.authorWhittaker, SRen_US
dc.contributor.authorBarlow, Cen_US
dc.contributor.authorMartin, MPen_US
dc.contributor.authorMancusi, Cen_US
dc.contributor.authorWagner, Sen_US
dc.contributor.authorSelf, Aen_US
dc.contributor.authorBarrie, Een_US
dc.contributor.authorTe Poele, Ren_US
dc.contributor.authorSharp, Sen_US
dc.contributor.authorBrown, Nen_US
dc.contributor.authorWilson, Sen_US
dc.contributor.authorJackson, Wen_US
dc.contributor.authorFischer, PMen_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorWalton, MIen_US
dc.contributor.authorMcDonald, Een_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorNoble, Men_US
dc.contributor.authorGarrett, MDen_US
dc.contributor.authorWorkman, Pen_US
dc.date.accessioned2017-11-06T11:59:12Z
dc.date.issued2018-03en_US
dc.identifier.citationMolecular oncology, 2018, 12 (3), pp. 287 - 304en_US
dc.identifier.issn1574-7891en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/899
dc.identifier.eissn1878-0261en_US
dc.identifier.doi10.1002/1878-0261.12148en_US
dc.description.abstractDeregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X-ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II, and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small-molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.en_US
dc.formatPrint-Electronicen_US
dc.format.extent287 - 304en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectHCT116 Cellsen_US
dc.subjectHT29 Cellsen_US
dc.subjectHumansen_US
dc.subjectMelanomaen_US
dc.subjectSulfonamidesen_US
dc.subjectAniline Compoundsen_US
dc.subjectPurinesen_US
dc.subjectRetinoblastoma Proteinen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectApoptosisen_US
dc.subjectCell Proliferationen_US
dc.subjectCyclin-Dependent Kinase 9en_US
dc.subjectCyclin-Dependent Kinase 2en_US
dc.subjectMyeloid Cell Leukemia Sequence 1 Proteinen_US
dc.titleMolecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-10-07en_US
rioxxterms.versionofrecord10.1002/1878-0261.12148en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-03en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMolecular oncologyen_US
pubs.issue3en_US
pubs.notesNo embargoen_US
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/Molecular Drug Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Cell Cycle Control (including GCLP Biomarker Group)
pubs.publication-statusPublisheden_US
pubs.volume12en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamMolecular Drug Resistanceen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamCell Cycle Control (including GCLP Biomarker Group)en_US
dc.contributor.icrauthorWhittaker, Stevenen_US
dc.contributor.icrauthorBrown, Nathanen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorGarrett, Michelle Dawnen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/