dc.contributor.author | Mallinger, A | |
dc.contributor.author | Schiemann, K | |
dc.contributor.author | Rink, C | |
dc.contributor.author | Sejberg, J | |
dc.contributor.author | Honey, MA | |
dc.contributor.author | Czodrowski, P | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Poeschke, O | |
dc.contributor.author | Busch, M | |
dc.contributor.author | Schneider, R | |
dc.contributor.author | Schwarz, D | |
dc.contributor.author | Musil, D | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Urbahns, K | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Wienke, D | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2016-11-18T16:02:47Z | |
dc.date.issued | 2016-06-09 | |
dc.identifier.citation | ACS medicinal chemistry letters, 2016, 7 (6), pp. 573 - 578 | |
dc.identifier.issn | 1948-5875 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/209 | |
dc.identifier.eissn | 1948-5875 | |
dc.identifier.doi | 10.1021/acsmedchemlett.6b00022 | |
dc.description.abstract | We 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. | |
dc.format | Electronic-eCollection | |
dc.format.extent | 573 - 578 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.title | 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-03-28 | |
rioxxterms.versionofrecord | 10.1021/acsmedchemlett.6b00022 | |
rioxxterms.licenseref.startdate | 2016-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | ACS medicinal chemistry letters | |
pubs.issue | 6 | |
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/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/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
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 | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Raynaud, Florence | |