Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability

Here we report the discovery of ABBV-744, a first in class, highly potent and selective inhibitor of BET family BD2 domains with drug like properties. ChIP-seq analysis revealed that ABBV-744 displaced BRD4 from AR-containing super enhancers and elicited potent inhibition of AR-dependent transcription without causing broad transcription alterations associated with exposure to pan BET inhibitors. BRD4 ChIP-Seq under four different treatment conditions in two cell lines. H3K27Ac ChIP-Seq from two cell lines, vehicle treatment only. AR ChIP-Seq in one cell line (LNCaP) with three treatment conditions. BRD4 and AR ChIP-Seq were all spike-in controlled.