Structure-Activity Relationship Study of N6-Benzoyladenine-Type BRD4 Inhibitors and Their Effects on Cell Differentiation and TNF-α Production

Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N-6-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-alpha production by THP-1 cells.