Bromodomains as therapeutic targets

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.

Figure 1

Phylogenetic tree of the human bromodomain family and substrate recognition of bromodomains. (a) Phylogenetic tree based on sequence alignments of predicted BRDs. For targets with multiple BRDs, the domains have been numbered starting from the N-terminus and the number is shown in parentheses. (b) Interaction of mouse BRD4 (Ref. 117) and mouse BRDT (Ref. 118) with monoacetylated Lys14 in histone H3 and a diacetylated H4 peptide monoacetylated on both Lys5 and Lys8. (c) Surface representation in similar orientation. See Table 1 for an explanation of protein symbols.

Figure 2

Domain organisation of bromodomain proteins and translocations in cancer. BRD modules are shown in green (labelled BRD). Other domain types are labelled directly in the figure and breakpoints are indicated by arrows. Wild-type domain arrangements are shown in the upper panel. See Table 1 for an explanation of protein symbols.

Figure 3

Structural overview of a bromodomain and binding mode of bromodomain inhibitors. (a) Ribbon diagram of the first BRD of BRD4. The main structural elements as well as the acetyl lysine binding site residues are labelled. (b) Superimposition of a diacetylated BET substrate peptide and the inhibitor JQ1. Inhibitor and peptide molecules are shown in stick representation and are coloured according to atom types. (c) Binding of JQ1 to the bromodomain of BRD4. Conserved water molecules in the active site are highlighted and hydrogen bonds are shown as dashed lines. (d) Complex of ischemin with CREBBP (Ref. 176).

Figure 4

Chemical structures of bromodomain inhibitors. Specificity and dissociation constants are also indicated.