دورية أكاديمية
Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
| العنوان: | Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases |
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| المؤلفون: | Clarke, Paul A, Ortiz-Ruiz, Maria-Jesus, TePoele, Robert, Adeniji-Popoola, Olajumoke, Box, Gary, Court, Will, Czasch, Stephanie, El Bawab, Samer, Esdar, Christina, Ewan, Ken, Gowan, Sharon, De Haven Brandon, Alexis, Hewitt, Phillip, Hobbs, Stephen M, Kaufmann, Wolfgang, Mallinger, Aurélie, Raynaud, Florence, Roe, Toby, Rohdich, Felix, Schiemann, Kai, Simon, Stephanie, Schneider, Richard, Valenti, Melanie, Weigt, Stefan, Blagg, Julian, Blaukat, Andree, Dale, Trevor C, Eccles, Suzanne A, Hecht, Stefan, Urbahns, Klaus, Workman, Paul, Wienke, Dirk |
| المساهمون: | Breast Cancer Now, Cancer Research UK |
| المصدر: | eLife ; volume 5 ; ISSN 2050-084X |
| بيانات النشر: | eLife Sciences Publications, Ltd |
| سنة النشر: | 2016 |
| المجموعة: | eLife (E-Journal - via CrossRef) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.7554/elife.20722 |
| الإتاحة: | https://doi.org/10.7554/elife.20722Test https://cdn.elifesciences.org/articles/20722/elife-20722-v3.pdfTest https://cdn.elifesciences.org/articles/20722/elife-20722-v3.xmlTest https://elifesciences.org/articles/20722Test |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.63194FE5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.7554/elife.20722 |
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