Failure to appropriately control gene expression is a salient feature of most human diseases. Therefore, the field of epigenetic therapeutics has rapidly grown into one of the most active areas of drug discovery. This is fueled by the fact that there exist hundreds of so-called druggable (by small molecules) epigenetic targets, many of which affect the state of chromatin and therefore gene expression. The result of this type of drug action, exemplified here by bromodomain inhibitors, is typically an alteration of the expression of a number of genes (up- as well as down-regulation). While some genes are more susceptible to this type of regulation, there is marked context dependency that represents both a challenge and an opportunity to drug hunters.

The bromodomain module, a critical component of epigenetic regulation, selectively recognizes acetylated lysine residues present in both histone and non-histone proteins. In human cells, there exist 46 proteins that contain bromodomain(s). The dysregulation of these so-called protein reader functions, and the genes that they control downstream, have been implicated in the development of a variety of diseases, making them attractive targets for drug discovery. It has been known for about a decade that small molecules are capable of binding to a bromodomain and the number of reported inhibitors has expanded dramatically in the past few years. The profound and broad pharmacology of bromodomain inhibition, especially that associated with targeting the so-called BET subfamily of bromodomains (BRD2, BRD3, BRD4, and BRDT), has led to the progression of a number of small molecules into the clinic for liquid as well as solid tumors. However, these BET bromodomain inhibitors may also have utility for non-malignant diseases of the nervous system.

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