Bromodomains as therapeutic targets

Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.
Expert Reviews in Molecular Medicine (Impact Factor: 5.91). 10/2011; 13:e29. DOI: 10.1017/S1462399411001992
Source: PubMed

ABSTRACT Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that 'write' (histone acetyltransferases, HATs) and 'erase' (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the 'reading process' mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (K(ac)) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues.

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Available from: Stefan Knapp, Jan 22, 2014
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    • "(continued on next page) P. Filippakopoulos, S. Knapp / FEBS Letters 586 (2012) 2692–2704 2697 protein 1 (BRPF1) [66] and two AAA domain containing protein (ATAD2) [67] as well as the KIAA1240 protein (KIAA1240) the bromodomain containing 9 (BRD9) and the bromodomain and PHD fingercontaining protein 3 (BRPF3). BRDs of this family have not been extensively studied for binding to acetylated proteins although their involvement in disease has been described and their target sites will contribute to better understanding of their function [34]. The BRD of ATAD2 has been shown to immunoprecipitate histone H3 (K14 ac [68]) but this interaction has not been quantified yet, while the closely homologous KIAA1240 binds to histone H4 (K5 ac [33] [69]). "
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