Targeting Low-Druggability Bromodomains: Fragment Based Screening and Inhibitor Design against the BAZ2B Bromodomain
نویسندگان
چکیده
منابع مشابه
Targeting Low-Druggability Bromodomains: Fragment Based Screening and Inhibitor Design against the BAZ2B Bromodomain
Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which have proven druggable, bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fr...
متن کاملStructure Enabled Design of BAZ2-ICR, A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B
The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stackin...
متن کامل“Fragment-Based Drug Design of Bromodomain Ligands”
Epigenetic mechnisms are essential for normal development and alterations of epigenetic processe are correlated with many human diseases, e.g., cancer. One of the important epigenetic modifications, acetylation of lysine, is mainly recognized by structurally conserved protein module bromodomains. Targeting bromodomains by small molecules is an emerging therapeutic strategy for cancer treatment....
متن کاملHigh-Throughput Fragment Docking into the BAZ2B Bromodomain: Efficient in Silico Screening for X-Ray Crystallography.
Bromodomains are protein modules that bind to acetylated lysine side chains in histones and other proteins. The bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) has been reported to be poorly druggable. Here, we screened an in-house library of 350 fragments by automatic docking to the BAZ2B bromodomain. The top 12 fragments according to the predicted binding energy were selected fo...
متن کاملFragment-Based Screening of the Bromodomain of ATAD2
Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.
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ژورنال
عنوان ژورنال: Journal of Medicinal Chemistry
سال: 2013
ISSN: 0022-2623,1520-4804
DOI: 10.1021/jm401582c