Description: PLX51107 is a novel, potent and selective BET (Bromodomain and Extra-Terminal motif) inhibitor, also called BRD4 (bromodomain and extra terminal domain) inhibitor with Kd values of 1.6, 2.1, 1.7, and 5 nM for BD1 and 5.9, 6.2, 6.1, and 120 nM for BD2 of BRD2, BRD3, BRD4, and BRDT, respectively; BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. PLX51107 also interacts with the bromodomains of CBP and EP300 with Kd in the 100 nM range. As a structurally distinct BET inhibitor, PLX51107 demonstrated potent in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. PLX51107 binds to the acetylated lysine recognition motifs in the bromodomains of the BRD4 protein, thereby preventing the binding of BRD4 to acetylated lysines on histones, which disrupts chromatin remodeling and gene expression. The discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.