Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype
| Autor: | James M. Woolven, William J. Kerr, Chun-wa Chung, Bhumika Karamshi, Beata S. Wyspiańska, John Evans, Emmanuel Hubert Demont, Laurie Gordon, Matthew J Lindon, Peter E. Soden, Rob Willis, Leanne Cutler, Darren J. Mitchell, Christopher Roland Wellaway, Antonia J. Lewis, Robert J. Watson, Paul Bamborough, Simon Taylor, Inmaculada Rioja, Sharon G. Bernard, Rab K. Prinjha, Peter D. Craggs |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
BRD4 medicine.drug_class Anti-Inflammatory Agents Cell Cycle Proteins Molecular Dynamics Simulation Quinolones 01 natural sciences Anti-inflammatory BET inhibitor 03 medical and health sciences Mice Protein Domains Cell Line Tumor Drug Discovery medicine Animals Humans QD Epigenetics Phylogeny 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites Small molecule Phenotype 0104 chemical sciences Amino acid Bromodomain Cell biology 010404 medicinal & biomolecular chemistry chemistry Drug Design Leukocytes Mononuclear Molecular Medicine Cytokines Half-Life Transcription Factors |
| ISSN: | 0022-2623 |
| Popis: | The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects. |
| Databáze: | OpenAIRE |
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