Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy

Abstract

Histone lysine acetylation is critical in regulating transcription. Dysregulation of this process results in aberrant gene expression in various diseases, including cancer. The bromodomain, present in several proteins, recognizes promotor lysine acetylation and recruits other transcription factors. The bromodomain extra-terminal (BET) family of proteins consists of four conserved mammalian members that regulate transcription of oncogenes such as MYC and the NUT fusion oncoprotein. Targeting the acetyl-lysine-binding property of BET proteins is a potential therapeutic approach of cancer. Consequently, following the demonstration that thienotriazolodiazepine small molecules effectively inhibit BET, clinical trials were initiated. We thus discuss the mechanisms of action of various BET inhibitors and the prospects for their clinical use as cancer therapeutics.

Keywords: BET inhibitors; BET protein; cancer; clinical trials; combination therapy; hematological malignancies; solid tumors; targeted therapy.

Figure 1.. Biology of bromodomain and extra-terminal inhibitors and their role in cancer therapy.

BET protein binds to acetylated histones and recruits, via its BRD4 domain, PTEF-b to sites of active transcription of growth-promoting genes such as MYC and NUT. In addition, the ET domain of BRD4 independently recruits transcriptional activators such as NSD3, JMJD6 and CHD4 to further increase rates of transcription. BET inhibitors block the initial binding of BET proteins to acetylated histones, and thus halts the transcriptional cascade of oncogenes. BET: Bromodomain and extra-terminal; PTEF-b: Positive transcriptional elongation factor complex.