BRD4 Bromodomain 1 Inhibitor Screening Using A Homogeneous Proximity Assay

By Pete Brescia, Brad Larson, and Peter Banks, BioTek Instruments, Inc., and D. Bochar and L. Blazer, Cayman Chemical Co.

Post-translational histone modifications are critical for modulation of chromatin structure by direct DNA interaction and indirect molecular interactions with recruited nuclear proteins. Chromatin structure modulation is proven necessary for gene regulation, repair and cell cycle progression and other processes. Bromodomains are small nuclear proteins that selectively bind to acetylated lysine residues of histone proteins. Once bound, these bromodomains recruit protein complexes involved in chromatin structure regulation, and thus play a role in gene expression. The bromodomain and extra-terminal (BET) protein family includes BRD2, BRD3, BRD4 and BRDT. These proteins all play key roles in diverse cellular processes, such as inflammatory gene expression, mitosis and viral/host interactions, by linking acetylation marks to transcriptional regulation at promoters. Small molecule inhibitors disrupt bromodomain/ histone interactions, holding promise as potential therapeutics for human disease.