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 (Kac) 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