dc.contributor.author | Clarke, PA | |
dc.contributor.author | Ortiz-Ruiz, M-J | |
dc.contributor.author | TePoele, R | |
dc.contributor.author | Adeniji-Popoola, O | |
dc.contributor.author | Box, G | |
dc.contributor.author | Court, W | |
dc.contributor.author | Czasch, S | |
dc.contributor.author | El Bawab, S | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Ewan, K | |
dc.contributor.author | Gowan, S | |
dc.contributor.author | De Haven Brandon, A | |
dc.contributor.author | Hewitt, P | |
dc.contributor.author | Hobbs, SM | |
dc.contributor.author | Kaufmann, W | |
dc.contributor.author | Mallinger, A | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Roe, T | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Schiemann, K | |
dc.contributor.author | Simon, S | |
dc.contributor.author | Schneider, R | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Weigt, S | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Blaukat, A | |
dc.contributor.author | Dale, TC | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Hecht, S | |
dc.contributor.author | Urbahns, K | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Wienke, D | |
dc.date.accessioned | 2019-01-25T09:50:38Z | |
dc.date.issued | 2016-12-09 | |
dc.identifier.citation | eLife, 2016, 5 | |
dc.identifier.issn | 2050-084X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3022 | |
dc.identifier.eissn | 2050-084X | |
dc.identifier.doi | 10.7554/elife.20722 | |
dc.description.abstract | Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. | |
dc.format | Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELIFE SCIENCES PUBLICATIONS LTD | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neoplasms | |
dc.subject | Disease Models, Animal | |
dc.subject | Hyperplasia | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | Anti-Inflammatory Agents | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Treatment Outcome | |
dc.subject | Cyclin-Dependent Kinase 8 | |
dc.subject | Mediator Complex | |
dc.subject | Heterografts | |
dc.title | Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-11-29 | |
rioxxterms.versionofrecord | 10.7554/elife.20722 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-12-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | eLife | |
pubs.notes | No embargo | |
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/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.publication-status | Published | |
pubs.volume | 5 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Gowan, Sharon | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Workman, Paul | |