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.

BET bromodomain inhibitors can influence the differentiation and maturation of a variety of cell types. Indeed, anti-cancer effects, mediated primarily by modulation of BRD4, have been the main driver of drug discovery thus far. For example, strong inhibitor efficacy can be observed in models of glioblastoma, which has stimulated the discovery of novel ligands with high brain exposure (Pastori et al, 2015). Moreover, much interest has been placed on immunomodulatory activities including altered expression of a number of cytokines. Indeed, BET bromodomain inhibitors hold promise to be used for the treatment of brain disorders characterized by neuroinflammation, including Alzheimer’s disease (Magistri et al, 2016).

Like other epigenetic modulators, BET bromodomains could conceivably be employed to correct single gene disorders. An example thereof is the hexanucleotide repeat expansion residing within the C9ORF72 gene, representing the most common known cause of amyotrophic lateral sclerosis (ALS). Indeed, BET bromodomain inhibitors increase the expression of C9ORF72 mRNA and pre-mRNA and may therefore compensate for haploinsufficiency without increasing the production of toxic RNA and protein products (Zeier et al, 2015).

Moreover, epigenetic phenomena have often implicated in memory as well as addiction. Korb et al, 2015 demonstrated that BRD4 provides a critical link between neuronal activation and the transcriptional responses that occur during memory formation.

In recent studies, we observed that BRD4 is elevated in the nucleus accumbens and recruited to promoter regions of addiction-related genes following repeated cocaine administration, and that inhibition of BRD4 attenuates transcriptional and behavioral responses to cocaine (Sartor et al, 2015). Thus, it is possible that bromodomain inhibitors may have therapeutic utility in the treatment of cocaine and perhaps other addictions.

Importantly, it must be noted that epigenetic drug will affect the expression of a number of genes and that the undesired effects can arise as a consequence (eg, Sullivan et al, 2015). However, it is reasonable to assume that the most critical period for putative adverse effects would occur early in development.

In conclusion, a variety of epigenetic drug candidates—mostly thanks to efforts in the cancer field—have recently become available to the field of neuroscience. This offers a tremendous opportunity that must be seized. This brief piece has focused on BET bromodomain inhibitors that display interesting effects. However, these are still early days and additional studies are still needed.

Funding and disclosure

The author declares no conflict of interest.