Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
| العنوان: | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
|---|---|
| المؤلفون: | Frank Fontaine, Angela A. Salim, Mehdi Moustaqil, Mark S. Butler, Wayne A. Johnston, Timothy L. Bailey, Benjamin M. Hogan, Kirill Alexandrov, Johannes Zuegg, Kelly A. Holmes, Emmanuelle Lesieur, Brian L. Black, Peter Koopman, Avril A. B. Robertson, Emma Sierecki, Mathias Francois, Deepak Mittal, Sreeman K. Mamidyala, Yann Gambin, Jeroen Overman, Sarah De Val, Jason S. Carroll, Ashley Robinson, Robert J. Capon, Mark J. Smyth, Ralf Jauch, Natalia Sacilotto, Mark E. Cooper |
| المساهمون: | Black, Brian L [0000-0002-6664-8913], Carroll, Jason S [0000-0003-3643-0080], Gambin, Yann [0000-0001-7378-8976], Francois, Mathias [0000-0002-9846-6882], Apollo - University of Cambridge Repository |
| المصدر: | eLife eLife, Vol 6 (2017) |
| بيانات النشر: | eLife Sciences Publications, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Proteomics, 0301 basic medicine, Transcription, Genetic, Mouse, protein-protein interactions, Regulator, Bioinformatics, Interactome, Biochemistry, chemistry.chemical_compound, Mice, tumour angiogenesis, Gene expression, SOXF Transcription Factors, Biology (General), Zebrafish, biology, General Neuroscience, food and beverages, Genomics, General Medicine, 3. Good health, small molecules, Treatment Outcome, Tumor Angiogenesis, Medicine, Stem cell, Insight, QH301-705.5, Science, Short Report, Antineoplastic Agents, Breast Neoplasms, Biophysical Phenomena, General Biochemistry, Genetics and Molecular Biology, Protein–protein interaction, developmental biology, 03 medical and health sciences, stem cells, transcription factors, protein protein interactions, Animals, Humans, Transcription factor, General Immunology and Microbiology, fungi, Zebrafish Proteins, biology.organism_classification, Disease Models, Animal, 030104 developmental biology, Developmental Biology and Stem Cells, chemistry, Gene Expression Regulation, Cancer research, gene expression, Blood Vessels, DNA |
| الوصف: | Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics. DOI: http://dx.doi.org/10.7554/eLife.21221.001Test |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4aebb132f8bf3ff1fd2499b265d05fbbTest https://ora.ox.ac.uk/objects/uuid:a6b10b1a-0443-4a8b-b926-8632e59228c5Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4aebb132f8bf3ff1fd2499b265d05fbb |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |