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dc.contributor.authorChan, F
dc.contributor.authorSun, C
dc.contributor.authorPerumal, M
dc.contributor.authorNguyen, Q-D
dc.contributor.authorBavetsias, V
dc.contributor.authorMcDonald, E
dc.contributor.authorMartins, V
dc.contributor.authorWilsher, NE
dc.contributor.authorRaynaud, FI
dc.contributor.authorValenti, M
dc.contributor.authorEccles, S
dc.contributor.authorTe Poele, R
dc.contributor.authorWorkman, P
dc.contributor.authorAboagye, EO
dc.contributor.authorLinardopoulos, S
dc.date.accessioned2018-06-27T09:02:56Z
dc.date.issued2007-12
dc.identifier.citationMolecular cancer therapeutics, 2007, 6 (12 Pt 1), pp. 3147 - 3157
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1940
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-07-2156
dc.description.abstractThe Aurora family of serine/threonine kinases is important for the regulation of centrosome maturation, chromosome segregation, and cytokinesis during mitosis. Overexpression of Aurora kinases in mammalian cells leads to genetic instability and transformation. Increased levels of Aurora kinases have also been linked to a broad range of human tumors. Here, we describe the properties of CCT129202, a representative of a structurally novel series of imidazopyridine small-molecule inhibitors of Aurora kinase activity. This compound showed high selectivity for the Aurora kinases over a panel of other kinases tested and inhibits proliferation in multiple cultured human tumor cell lines. CCT129202 causes the accumulation of human tumor cells with >or=4N DNA content, leading to apoptosis. CCT120202-treated human tumor cells showed a delay in mitosis, abrogation of nocodazole-induced mitotic arrest, and spindle defects. Growth of HCT116 xenografts in nude mice was inhibited after i.p. administration of CCT129202. We show that p21, the cyclin-dependent kinase inhibitor, is induced by CCT129202. Up-regulation of p21 by CCT129202 in HCT116 cells led to Rb hypophosphorylation and E2F inhibition, contributing to a decrease in thymidine kinase 1 transcription. This has facilitated the use of 3'-deoxy-3'[(18)F]fluorothymidine-positron emission tomography to measure noninvasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo.
dc.formatPrint
dc.format.extent3147 - 3157
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectImidazoles
dc.subjectPyridines
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectRetinoblastoma Protein
dc.subjectHistones
dc.subjectEnzyme Inhibitors
dc.subjectMicroscopy, Fluorescence
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectOligonucleotide Array Sequence Analysis
dc.subjectMitosis
dc.subjectApoptosis
dc.subjectDown-Regulation
dc.subjectPhosphorylation
dc.subjectFemale
dc.subjectTumor Suppressor Protein p53
dc.subjectAurora Kinases
dc.titleMechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.
dc.typeJournal Article
rioxxterms.versionofrecord10.1158/1535-7163.mct-07-2156
rioxxterms.licenseref.startdate2007-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue12 Pt 1
pubs.notesNot known
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
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/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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
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/Tumour Biology & Metastasis
pubs.publication-statusPublished
pubs.volume6
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamTumour Biology & Metastasisen_US
dc.contributor.icrauthorBavetsias, Vassiliosen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorEccles, Suzanneen
dc.contributor.icrauthorWorkman, Paulen


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