dc.contributor.author | Whittaker, SR | |
dc.contributor.author | Barlow, C | |
dc.contributor.author | Martin, MP | |
dc.contributor.author | Mancusi, C | |
dc.contributor.author | Wagner, S | |
dc.contributor.author | Self, A | |
dc.contributor.author | Barrie, E | |
dc.contributor.author | Te Poele, R | |
dc.contributor.author | Sharp, S | |
dc.contributor.author | Brown, N | |
dc.contributor.author | Wilson, S | |
dc.contributor.author | Jackson, W | |
dc.contributor.author | Fischer, PM | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Walton, MI | |
dc.contributor.author | McDonald, E | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Noble, M | |
dc.contributor.author | Garrett, MD | |
dc.contributor.author | Workman, P | |
dc.date.accessioned | 2017-11-06T11:59:12Z | |
dc.date.issued | 2018-03-01 | |
dc.identifier.citation | Molecular oncology, 2018, 12 (3), pp. 287 - 304 | |
dc.identifier.issn | 1574-7891 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/899 | |
dc.identifier.eissn | 1878-0261 | |
dc.identifier.doi | 10.1002/1878-0261.12148 | |
dc.description.abstract | Deregulation 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.format | Print-Electronic | |
dc.format.extent | 287 - 304 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | HCT116 Cells | |
dc.subject | HT29 Cells | |
dc.subject | Humans | |
dc.subject | Melanoma | |
dc.subject | Sulfonamides | |
dc.subject | Aniline Compounds | |
dc.subject | Purines | |
dc.subject | Retinoblastoma Protein | |
dc.subject | Antineoplastic Agents | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Cyclin-Dependent Kinase 9 | |
dc.subject | Cyclin-Dependent Kinase 2 | |
dc.subject | Myeloid Cell Leukemia Sequence 1 Protein | |
dc.title | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-10-07 | |
rioxxterms.versionofrecord | 10.1002/1878-0261.12148 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-03 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular oncology | |
pubs.issue | 3 | |
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/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-status | Published | |
pubs.volume | 12 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Molecular Drug Resistance | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Cell Cycle Control (including GCLP Biomarker Group) | |
dc.contributor.icrauthor | Whittaker, Steven | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Garrett, Michelle Dawn | |
dc.contributor.icrauthor | Workman, Paul | |