dc.contributor.author | Czodrowski, P | |
dc.contributor.author | Mallinger, A | |
dc.contributor.author | Wienke, D | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Pöschke, O | |
dc.contributor.author | Busch, M | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Ortiz-Ruiz, M-J | |
dc.contributor.author | Schneider, R | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Musil, D | |
dc.contributor.author | Schwarz, D | |
dc.contributor.author | Dale, T | |
dc.contributor.author | Urbahns, K | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Schiemann, K | |
dc.date.accessioned | 2016-11-23T14:36:34Z | |
dc.date.issued | 2016-10-27 | |
dc.identifier.citation | Journal of medicinal chemistry, 2016, 59 (20), pp. 9337 - 9349 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/266 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.6b00597 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 9337 - 9349 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Neoplasms, Experimental | |
dc.subject | Imidazoles | |
dc.subject | Thiadiazoles | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Cell Proliferation | |
dc.subject | Molecular Structure | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Female | |
dc.subject | Drug Discovery | |
dc.subject | Cyclin-Dependent Kinase 8 | |
dc.subject | High-Throughput Screening Assays | |
dc.subject | Biomarkers, Tumor | |
dc.title | Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-05 | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.6b00597 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-10-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 20 | |
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/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-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 | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Clarke, Paul | |