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dc.contributor.authorMallinger, A
dc.contributor.authorSchiemann, K
dc.contributor.authorRink, C
dc.contributor.authorStieber, F
dc.contributor.authorCalderini, M
dc.contributor.authorCrumpler, S
dc.contributor.authorStubbs, M
dc.contributor.authorAdeniji-Popoola, O
dc.contributor.authorPoeschke, O
dc.contributor.authorBusch, M
dc.contributor.authorCzodrowski, P
dc.contributor.authorMusil, D
dc.contributor.authorSchwarz, D
dc.contributor.authorOrtiz-Ruiz, M-J
dc.contributor.authorSchneider, R
dc.contributor.authorThai, C
dc.contributor.authorValenti, M
dc.contributor.authorde Haven Brandon, A
dc.contributor.authorBurke, R
dc.contributor.authorWorkman, P
dc.contributor.authorDale, T
dc.contributor.authorWienke, D
dc.contributor.authorClarke, PA
dc.contributor.authorEsdar, C
dc.contributor.authorRaynaud, FI
dc.contributor.authorEccles, SA
dc.contributor.authorRohdich, F
dc.contributor.authorBlagg, J
dc.date.accessioned2020-06-26T08:27:41Z
dc.date.issued2016-02
dc.identifier.citationJournal of medicinal chemistry, 2016, 59 (3), pp. 1078 - 1101
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3774
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/acs.jmedchem.5b01685en_US
dc.description.abstractThe Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
dc.formatPrint-Electronic
dc.format.extent1078 - 1101
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCaco-2 Cells
dc.subjectAnimals
dc.subjectDogs
dc.subjectHumans
dc.subjectMice
dc.subjectRats
dc.subjectRats, Wistar
dc.subjectNeoplasms, Experimental
dc.subjectAminopyridines
dc.subjectCyclin-Dependent Kinases
dc.subjectAdministration, Oral
dc.subjectXenograft Model Antitumor Assays
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectBiological Availability
dc.subjectDose-Response Relationship, Drug
dc.subjectSolubility
dc.subjectModels, Molecular
dc.subjectFemale
dc.subjectMale
dc.subjectSmall Molecule Libraries
dc.subjectDrug Discovery
dc.subjectCyclin-Dependent Kinase 8
dc.titleDiscovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jmedchem.5b01685
rioxxterms.licenseref.startdate2016-02en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of medicinal chemistry
pubs.issue3
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/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/Cancer Therapeutics/Tumour Biology & Metastasis
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
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/Cancer Therapeutics/Tumour Biology & Metastasis
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-statusPublished
pubs.volume59en_US
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamTumour Biology & Metastasisen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorEccles, Suzanneen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorBurke, Rosemaryen
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorWorkman, Paulen


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