BROMOscan high throughput, quantitative ligand binding assays identify best in class bromodomain inhibitors from a screen of mature compounds thought to specifically target other protein classes

BROMOscan high throughput, quantitative ligand binding assays identify best in class bromodomain inhibitors from a screen of mature compounds thought to specifically target other protein classes
Version:
0313

File Name/Number:
AACR

Year:
2013

Post-translationally appended acetyl-lysine marks on histone tails are key regulatory features of the epigenetic code. Bromodomains are “readers” of this specific lysine acetylation code, playing an important role in chromatin remodeling and regulation of gene expression. Bromodomains have emerged as an important new druggable target class in small-molecule inhibitor drug discovery, and several bromodomain-containing proteins have been associated with disease. There are 57 bromodomains contained in 41 different proteins; however, few small molecule bromodomain inhibitors have been reported. One primary factor limiting the discovery of new inhibitors is the absence of a comprehensive biochemical bromodomain screening platform. Here we describe the application of DiscoveRx Corporation’s proven ligand binding assay technology (KINOMEscan) to the development of quantitative ligand binding assays for human bromodomains (BROMOscan). We have developed a carefully validated assay panel that covers >30 percent of the human bromodomain family, and this panel is suitable for HTS, selectivity profiling, and quantitative affinity (Kd) assessment. We have used this panel internally to identify novel bromodomain inhibitors and, remarkably, have demonstrated that known, mature inhibitors thought to be selective for targets from other protein families have best in class affinity for bromodomains as well. These data shall be presented, as will a description of the BROMOscan panel replete with extensive assay validation data.