Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins
| Autor: | Peter D. Craggs, Darren Jason Mitchell, Rab K. Prinjha, Alex Preston, James Michael Woolven, Laurie J. Gordon, Simon Taylor, Paul Bamborough, Chun-wa Chung, Paola Grandi, James Gray, Francesco Rianjongdee, Matthew J Lindon, Anne-Marie Michon, Emma J. Jones, Inmaculada Rioja, Robert J. Watson, Ian D. Wall, Stephen John Atkinson, Emmanuel Hubert Demont, Jonathan Thomas Seal |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Chemistry Protein domain Highly selective 01 natural sciences Phenotype In vitro 0104 chemical sciences Cell biology Bromodomain 010404 medicinal & biomolecular chemistry 03 medical and health sciences In vivo Drug Discovery Molecular Medicine Structure–activity relationship Binding site 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 63:9070-9092 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization. |
| Databáze: | OpenAIRE |
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