Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.
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| Title: | Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. |
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| Authors: | Gilan, Omer, Rioja, Inmaculada, Knezevic, Kathy, Bell, Matthew J., Yeung, Miriam M., Harker, Nicola R., Lam, Enid Y. N., Chung, Chun-wa, Bamborough, Paul, Petretich, Massimo, Urh, Marjeta, Atkinson, Stephen J., Bassil, Anna K., Roberts, Emma J., Vassiliadis, Dane, Burr, Marian L., Preston, Alex G. S., Wellaway, Christopher, Werner, Thilo, Gray, James R. |
| Source: | Science (pre-March 2025). 4/24/2020, Vol. 368 Issue 6489, p387-394. 8p. 5 Diagrams. |
| Subjects: | Bromodomains, Inflammation, Genetic transcription, Chromatin, Gene expression |
| Abstract: | The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies. [ABSTRACT FROM AUTHOR] |
| Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aaz8455 |
