dc.contributor.author | Mallinger, A | |
dc.contributor.author | Schiemann, K | |
dc.contributor.author | Rink, C | |
dc.contributor.author | Stieber, F | |
dc.contributor.author | Calderini, M | |
dc.contributor.author | Crumpler, S | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Adeniji-Popoola, O | |
dc.contributor.author | Poeschke, O | |
dc.contributor.author | Busch, M | |
dc.contributor.author | Czodrowski, P | |
dc.contributor.author | Musil, D | |
dc.contributor.author | Schwarz, D | |
dc.contributor.author | Ortiz-Ruiz, M-J | |
dc.contributor.author | Schneider, R | |
dc.contributor.author | Thai, C | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | de Haven Brandon, A | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Dale, T | |
dc.contributor.author | Wienke, D | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2020-06-26T08:27:41Z | |
dc.date.issued | 2016-02-11 | |
dc.identifier.citation | Journal of medicinal chemistry, 2016, 59 (3), pp. 1078 - 1101 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3774 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.5b01685 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 1078 - 1101 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Caco-2 Cells | |
dc.subject | Animals | |
dc.subject | Dogs | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Rats | |
dc.subject | Rats, Wistar | |
dc.subject | Neoplasms, Experimental | |
dc.subject | Aminopyridines | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | Administration, Oral | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Molecular Structure | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Biological Availability | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Solubility | |
dc.subject | Models, Molecular | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Small Molecule Libraries | |
dc.subject | Drug Discovery | |
dc.subject | Cyclin-Dependent Kinase 8 | |
dc.title | Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.5b01685 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-02 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 3 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 59 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Tumour Biology & Metastasis | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Eccles, Suzanne | |