Bromodomains as theraputic targets

Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.
Expert Reviews in Molecular Medicine (Impact Factor: 5.15). 10/2011; 13:e29. DOI: 10.1017/S1462399411001992
Source: PubMed


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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    • "Bromodomain-containing proteins have been identified as attractive therapeutic targets [3]. In order to assess the on-target effect of developed inhibitors in the intact cell, we employed FRAP experiments for a variety of these targets broadly covering the branches of the bromodomain tree [1] (Figure 1B). "
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    ABSTRACT: Background Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Bromdomains are the readers of acetylated histone marks, and, consequently, bromodomain-containing proteins have a variety of chromatin-related functions. Moreover, they are increasingly being recognised as important mediators of a wide range of diseases. The first potent and selective bromodomain inhibitors are beginning to be described, but the diverse or unknown functions of bromodomain-containing proteins present challenges to systematically demonstrating cellular efficacy and selectivity for these inhibitors. Here we assess the viability of fluorescence recovery after photobleaching (FRAP) assays as a target agnostic method for the direct visualisation of an on-target effect of bromodomain inhibitors in living cells. Results Mutation of a conserved asparagine crucial for binding to acetylated lysines in the bromodomains of BRD3, BRD4 and TRIM24 all resulted in reduction of FRAP recovery times, indicating loss of or significantly reduced binding to acetylated chromatin, as did the addition of known inhibitors. Significant differences between wild type and bromodomain mutants for ATAD2, BAZ2A, BRD1, BRD7, GCN5L2, SMARCA2 and ZMYND11 required the addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) to amplify the binding contribution of the bromodomain. Under these conditions, known inhibitors decreased FRAP recovery times back to mutant control levels. Mutation of the bromodomain did not alter FRAP recovery times for full-length CREBBP, even in the presence of SAHA, indicating that other domains are primarily responsible for anchoring CREBBP to chromatin. However, FRAP assays with multimerised CREBBP bromodomains resulted in a good assay to assess the efficacy of bromodomain inhibitors to this target. The bromodomain and extraterminal protein inhibitor PFI-1 was inactive against other bromodomain targets, demonstrating the specificity of the method. Conclusions Viable FRAP assays were established for 11 representative bromodomain-containing proteins that broadly cover the bromodomain phylogenetic tree. Addition of SAHA can overcome weak binding to chromatin, and the use of tandem bromodomain constructs can eliminate masking effects of other chromatin binding domains. Together, these results demonstrate that FRAP assays offer a potentially pan-bromodomain method for generating cell-based assays, allowing the testing of compounds with respect to cell permeability, on-target efficacy and selectivity.
    Epigenetics & Chromatin 07/2014; 7(1). DOI:10.1186/1756-8935-7-14 · 5.33 Impact Factor
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    • "The bromodomain (BRD) is a conserved protein motif of ~110 amino acids that recognizes and binds ε-N-acetylated lysine residues in histone and non-histone proteins. Through this interaction, bromodomain-containing proteins facilitate the anchoring of nuclear macromolecular complexes to specific acetylated nucleosome sites on chromatin and control several biological processes including DNA replication, DNA damage repair, chromatin remodeling, and transcription regulation (45). The bromodomain and extra-terminal (BET) family of proteins, defined by tandem BET domain, include BRD2, BRD3, BRD4, and BRDT. "
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    ABSTRACT: Acute lymphoblastic leukemia is the most common malignancy in children. Although it is now curable in 80-90% of cases, patients with T-cell acute lymphoblastic leukemia (T-ALL) experience a higher frequency of induction failure and early relapse. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-ALL will not be cured. As such, we are in need of new targeted therapies for the disease. Recent advances in the molecular characterization of T-ALL have uncovered a number of new therapeutic targets. This review will summarize recent advancements in the study of inhibiting the NOTCH1, PI3K-AKT, and Cyclin D3:CDK4/6 pathways as therapeutic strategies for T-ALL. We will focus on pre-clinical studies supporting the testing of small-molecule inhibitors targeting these proteins and the rationale of combination therapies. Moreover, epigenetic approaches to modulate T-ALL are rapidly emerging. Here, we will discuss the data supporting the role of bromodomain and extra-terminal bromodomain inhibitors in human T-ALL.
    Frontiers in Oncology 07/2014; 4:170. DOI:10.3389/fonc.2014.00170
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    • "The BET family proteins , especially BRD4, have recently been shown to play an important role in the pathways that cause multiple types of cancer , including acute myeloid leukemia (Zuber et al., 2011), mixed lineage leukemia (Dawson et al., 2011), multiple myeloma (Mertz et al., 2011), and an aggressive form of squamous carcinoma called NUT (nuclear protein in testis) midline carcinoma (Filippakopoulos et al., 2010; French et al., 2001, 2003, 2008; Reynoird et al., 2010). These clinically relevant studies have validated the BET bromodomains as attractive epigenetic cancer therapy targets and also displayed the need for potent and selective bromodomain inhibitors (Belkina and Denis, 2012; Furdas et al., 2012; Muller et al., 2011). "
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    ABSTRACT: Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control bromodomain-related gene expression in human diseases.
    Chemistry & biology 04/2014; 21(5). DOI:10.1016/j.chembiol.2014.03.004 · 6.65 Impact Factor
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