Bromodomains (BRDs) are epigenetic readers that specifically recognize the acetyl-lysine residues of histones. The role in chromatin remodeling and transcriptional regulation correlate these proteins to several disease states such cancer, inflammation, and viral infection, making them an excellent therapeutic target. The most studied and druggable family of BRD-containing proteins is the bromo and extra C-terminal domain (BET), whose members (BRD2, BRD3, BRD4, and BRDT) contain two highly homologous bromodomains: BD1 and BD2. Several reports have suggested that these domains have different functions and their selective inhibition could be beneficial in treating diseases or mitigating unwanted effects. To date, despite the extensive efforts, there is still a lack of powerful and selective inhibitors of bromodomain proteins, mainly due to the high homology not only between BET proteins but also between BD1 and BD2 domains. Here we describe the design, synthesis and preliminary biochemical evaluation of a new class of bivalent chemical probes of BET proteins. Using different spacers, we linked two different scaffolds: the RVX-208, a selective inhibitor of BD2 domain and a triazolobenzotriazepine-based compound, an inhibitor of BD1 domain. These compounds, simultaneously binding either BD1 or BD2 domains, will help clarify the differences between BD1 and BD2, allowing to get additional details on how these portions recognize the acetylated lysine residues of histones and other proteins.
|Titolo:||Design, synthesis and in vitro evaluation of bivalent chemical probes for bromo and extra-terminal domain (BET) proteins|
SBARDELLA, Gianluca (Corresponding)
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||4.3 Poster|