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dc.contributor.authorCzodrowski, P
dc.contributor.authorMallinger, A
dc.contributor.authorWienke, D
dc.contributor.authorEsdar, C
dc.contributor.authorPöschke, O
dc.contributor.authorBusch, M
dc.contributor.authorRohdich, F
dc.contributor.authorEccles, SA
dc.contributor.authorOrtiz-Ruiz, M-J
dc.contributor.authorSchneider, R
dc.contributor.authorRaynaud, FI
dc.contributor.authorClarke, PA
dc.contributor.authorMusil, D
dc.contributor.authorSchwarz, D
dc.contributor.authorDale, T
dc.contributor.authorUrbahns, K
dc.contributor.authorBlagg, J
dc.contributor.authorSchiemann, K
dc.date.accessioned2016-11-23T14:36:34Z
dc.date.issued2016-10-27
dc.identifier.citationJournal of medicinal chemistry, 2016, 59 (20), pp. 9337 - 9349
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/266
dc.identifier.eissn1520-4804
dc.identifier.doi10.1021/acs.jmedchem.6b00597
dc.description.abstractThe mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.
dc.formatPrint-Electronic
dc.format.extent9337 - 9349
dc.languageeng
dc.language.isoeng
dc.publisherAMER CHEMICAL SOC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectNeoplasms, Experimental
dc.subjectImidazoles
dc.subjectThiadiazoles
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectDrug Screening Assays, Antitumor
dc.subjectCell Proliferation
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectDose-Response Relationship, Drug
dc.subjectFemale
dc.subjectDrug Discovery
dc.subjectCyclin-Dependent Kinase 8
dc.subjectHigh-Throughput Screening Assays
dc.subjectBiomarkers, Tumor
dc.titleStructure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.
dc.typeJournal Article
dcterms.dateAccepted2016-08-05
rioxxterms.versionofrecord10.1021/acs.jmedchem.6b00597
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-10-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of medicinal chemistry
pubs.issue20
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/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
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/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume59
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
icr.researchteamMedicinal Chemistry 1
icr.researchteamSignal Transduction & Molecular Pharmacology
dc.contributor.icrauthorRaynaud, Florence
dc.contributor.icrauthorClarke, Paul


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