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: | Toby Roe, Will Court, Felix Rohdich, Julian Blagg, Wolfgang Kaufmann, Stefan Hecht, Richard Schneider, Stephen M. Hobbs, Christina Esdar, Alexis De Haven Brandon, Samer El Bawab, Phllip Hewitt, Suzanne A. Eccles, Kai Schiemann, Trevor Clive Dale, Paul Workman, Aurélie Mallinger, Stefan Weigt, Klaus Urbahns, Olajumoke Adeniji-Popoola, Andree Blaukat, Stephanie Simon, Robert TePoele, Melanie Valenti, Sharon Gowan, Stefanie Czasch, Paul A. Clarke, Gary Box, Dirk Wienke, Kenneth Burnside Ramsay Ewan, Maria-Jesus Ortiz-Ruiz, Florence I. Raynaud |
| المصدر: | eLife eLife, Vol 5 (2016) |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Anti-Inflammatory Agents, Pharmacology, Mice, Neoplasms, Biology (General), media_common, Cancer Biology, Mediator Complex, Kinase, General Neuroscience, Wnt signaling pathway, General Medicine, Cyclin-Dependent Kinases, inhibitor, Treatment Outcome, Medicine, Heterografts, Stem cell, Research Article, Human, Drug, QH301-705.5, Science, media_common.quotation_subject, CDK8, Antineoplastic Agents, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Wnt, Immune system, Cyclin-dependent kinase, super-enhancer, medicine, Animals, Humans, Human Biology and Medicine, Protein Kinase Inhibitors, Hyperplasia, General Immunology and Microbiology, Cancer, medicine.disease, Cyclin-Dependent Kinase 8, Disease Models, Animal, 030104 developmental biology, Cancer cell, biology.protein |
| 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. DOI: http://dx.doi.org/10.7554/eLife.20722.001 eLife digest Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumors often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs. Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signaling pathway – which enables cells to communicate with one another – and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumors, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood. Here Clarke, Ortiz-Ruiz et al. investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells. For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumors. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz et al. also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects. Clarke, Ortiz-Ruiz et al. conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers. DOI: http://dx.doi.org/10.7554/eLife.20722.002 |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2050-084X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::320a3dd4067dcc727c7a6157a8004c42 http://europepmc.org/articles/PMC5224920 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....320a3dd4067dcc727c7a6157a8004c42 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
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