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dc.contributor.authorMallinger, Aen_US
dc.contributor.authorSchiemann, Ken_US
dc.contributor.authorRink, Cen_US
dc.contributor.authorSejberg, Jen_US
dc.contributor.authorHoney, MAen_US
dc.contributor.authorCzodrowski, Pen_US
dc.contributor.authorStubbs, Men_US
dc.contributor.authorPoeschke, Oen_US
dc.contributor.authorBusch, Men_US
dc.contributor.authorSchneider, Ren_US
dc.contributor.authorSchwarz, Den_US
dc.contributor.authorMusil, Den_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorUrbahns, Ken_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorWienke, Den_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorEsdar, Cen_US
dc.contributor.authorRohdich, Fen_US
dc.contributor.authorBlagg, Jen_US
dc.date.accessioned2016-11-18T16:02:47Z
dc.date.issued2016-06en_US
dc.identifier.citationACS medicinal chemistry letters, 2016, 7 (6), pp. 573 - 578en_US
dc.identifier.issn1948-5875en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/209
dc.identifier.eissn1948-5875en_US
dc.identifier.doi10.1021/acsmedchemlett.6b00022en_US
dc.description.abstractWe demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1(SER727) phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing.en_US
dc.formatElectronic-eCollectionen_US
dc.format.extent573 - 578en_US
dc.languageengen_US
dc.language.isoengen_US
dc.title2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-03-28en_US
rioxxterms.versionofrecord10.1021/acsmedchemlett.6b00022en_US
rioxxterms.licenseref.startdate2016-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfACS medicinal chemistry lettersen_US
pubs.issue6en_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/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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
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.publication-statusPublisheden_US
pubs.volume7en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorBurke, Rosemaryen_US


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