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dc.contributor.authorCouty, Sen_US
dc.contributor.authorWestwood, IMen_US
dc.contributor.authorKalusa, Aen_US
dc.contributor.authorCano, Cen_US
dc.contributor.authorTravers, Jen_US
dc.contributor.authorBoxall, Ken_US
dc.contributor.authorChow, CLen_US
dc.contributor.authorBurns, Sen_US
dc.contributor.authorSchmitt, Jen_US
dc.contributor.authorPickard, Len_US
dc.contributor.authorBarillari, Cen_US
dc.contributor.authorMcAndrew, PCen_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorLinardopoulos, Sen_US
dc.contributor.authorGriffin, RJen_US
dc.contributor.authorAherne, GWen_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorJones, Ken_US
dc.contributor.authorvan Montfort, RLMen_US
dc.date.accessioned2018-05-24T10:20:26Z
dc.date.issued2013-10en_US
dc.identifier.citationOncotarget, 2013, 4 (10), pp. 1647 - 1661en_US
dc.identifier.issn1949-2553en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1688
dc.identifier.eissn1949-2553en_US
dc.identifier.doi10.18632/oncotarget.1255en_US
dc.description.abstractThe ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.en_US
dc.formatPrinten_US
dc.format.extent1647 - 1661en_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.subjectHumansen_US
dc.subjectImidazolesen_US
dc.subjectCyclic AMP-Dependent Protein Kinasesen_US
dc.subjectRibosomal Protein S6 Kinases, 90-kDaen_US
dc.subjectRecombinant Fusion Proteinsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectSignal Transductionen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectPhosphorylationen_US
dc.subjectDrug Designen_US
dc.subjectModels, Molecularen_US
dc.subjectUrinary Bladder Neoplasmsen_US
dc.subjectHigh-Throughput Screening Assaysen_US
dc.titleThe discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.18632/oncotarget.1255en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2013-10en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfOncotargeten_US
pubs.issue10en_US
pubs.notesNot knownen_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/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/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Structure-Based Drug Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structure-Based Drug Design
pubs.publication-statusPublisheden_US
pubs.volume4en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamDrug Target Discoveryen_US
icr.researchteamMedicinal Chemistry 3en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamHit Discovery & Structural Designen_US
icr.researchteamStructure-Based Drug Designen_US
dc.contributor.icrauthorVan Montfort, Roberten_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorLinardopoulos, Spyridonen_US
dc.contributor.icrauthorSchmitt, Jessica Andreaen_US
dc.contributor.icrauthorWestwood, Isaacen_US
dc.contributor.icrauthorJones, Keithen_US
dc.contributor.icrauthorTravers, Jonen_US


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