Targeting bromodomains: epigenetic readers of lysine acetylation

Key Points Bromodomains are acetyl-lysine-specific protein interaction modules present in proteins that have key roles in the regulation of gene transcription. Aberrant acetylation levels and dysfunction of bromodomain-containing proteins lead to deregulation of transcriptional programmes; this has been linked to the development of several diseases, including cancer, inflammation and viral infection. The recent discovery of potent and highly specific inhibitors for bromodomains of the BET family (BRD2, BRD3, BRD4 and BRDT) has stimulated intensive research activity in different therapeutic areas, particularly in oncology, where BET inhibitors have now entered clinical testing. Generally good druggability has also been predicted for non-BET bromodomains, which suggests that the bromodomain family may emerge as a major new target class for the development of new pharmaceuticals. Inhibiting bromodomains — which are small interaction modules on proteins that assemble acetylation-dependent transcriptional regulatory complexes — could be a way to alter the expression of disease-promoting genes. Here, the authors highlight recent developments in the discovery of small-molecule bromodomain inhibitors and discuss how they might be used in cancer, inflammation and viral infection. Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.