Recent Updates on Small Molecule Inhibitors of Bromo and Extra C-Terminal Domain (BET) Family of Bromodomains

Abstract

The bromo and extra C-terminal domain (BET) family of bromodomains (BRDs) are involved in binding epigenetic marks on histone proteins, more specifically ɛ-N-acetylated lysine residues. Inhibition of these targets leads to profound effects in relevant models of disease. BET BRDs inhibitors reported to date include benzodiazepines, benzotriazepines, 3,5-dimethylisoxoazole, dihydroquinazolinone, tetrahydroquinoline, thiazol-2-one, 4-acylpyrroles, diazobenzene, naphthyridines, and benzimidazole scaffold/moiety in their structure. Some potent inhibitors of BRD4, one of the bromodomain members, bind to asparagine140 residue of the acetylated-lysine site of BETs through triazole or isoxazole moieties. Some BET BRDs inhibitors also act as kinase inhibitors. Small molecules BET BRDs inhibitors have potential as anti-inflammatory, antiviral, and anticancer agents. Actions to produce a contraceptive for male rely on targeting BET family by a potent and selective bromodomain inhibitor. Several inhibitors targeting BRD4 are in preclinical/clinical trials as anticancer drugs.