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dc.contributor.authorWhittaker, SR
dc.contributor.authorBarlow, C
dc.contributor.authorMartin, MP
dc.contributor.authorMancusi, C
dc.contributor.authorWagner, S
dc.contributor.authorSelf, A
dc.contributor.authorBarrie, E
dc.contributor.authorTe Poele, R
dc.contributor.authorSharp, S
dc.contributor.authorBrown, N
dc.contributor.authorWilson, S
dc.contributor.authorJackson, W
dc.contributor.authorFischer, PM
dc.contributor.authorClarke, PA
dc.contributor.authorWalton, MI
dc.contributor.authorMcDonald, E
dc.contributor.authorBlagg, J
dc.contributor.authorNoble, M
dc.contributor.authorGarrett, MD
dc.contributor.authorWorkman, P
dc.date.accessioned2017-11-06T11:59:12Z
dc.date.issued2018-03-01
dc.identifier.citationMolecular oncology, 2018, 12 (3), pp. 287 - 304
dc.identifier.issn1574-7891
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/899
dc.identifier.eissn1878-0261
dc.identifier.doi10.1002/1878-0261.12148
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.
dc.formatPrint-Electronic
dc.format.extent287 - 304
dc.languageeng
dc.language.isoeng
dc.publisherWILEY
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHCT116 Cells
dc.subjectHT29 Cells
dc.subjectHumans
dc.subjectMelanoma
dc.subjectSulfonamides
dc.subjectAniline Compounds
dc.subjectPurines
dc.subjectRetinoblastoma Protein
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectCyclin-Dependent Kinase 9
dc.subjectCyclin-Dependent Kinase 2
dc.subjectMyeloid Cell Leukemia Sequence 1 Protein
dc.titleMolecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor.
dc.typeJournal Article
dcterms.dateAccepted2017-10-07
rioxxterms.versionofrecord10.1002/1878-0261.12148
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular oncology
pubs.issue3
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/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.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-statusPublished
pubs.volume12
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 1
icr.researchteamMolecular Drug Resistance
icr.researchteamSignal Transduction & Molecular Pharmacology
icr.researchteamCell Cycle Control (including GCLP Biomarker Group)
dc.contributor.icrauthorWhittaker, Steven
dc.contributor.icrauthorClarke, Paul
dc.contributor.icrauthorGarrett, Michelle Dawn
dc.contributor.icrauthorWorkman, Paul


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