I-BET726 is a highly selective inhibitor of BET family proteins with IC50 of 41 nM, 31 nM, and 22 nM for BRD2, BRD3, and BRD4, respectively.

I-BET726 is a novel small molecule inhibitor that binds to the acetyl-lysine recognition pocket of BET family proteins. It binds with high affinity to BRD2 (IC50= 41 nM), BRD3 (IC50= 31 nM), and BRD4 (IC50= 22 nM), and competes with tetra-acetylated histone H4 peptides (K5ac, K8ac, K12ac, K16ac) for binding to the bromodomains of these proteins. I-BET726 is highly selective for BET family proteins, exhibiting no binding affinity for any bromodomain-containing homolog tested with the exception of CREBBP, for which I-BET726 binds with >1000-fold lower affinity than to BET family proteins. Since potent anti-proliferative activity was observed for BET inhibitors in MYC-driven hematologic cancer models, we screened a panel of neuroblastoma cell lines, in which MYCN amplification is common, for effects on cell growth following I-BET726 treatment. All neuroblastoma cell lines tested exhibited potent growth inhibition, with a median growth IC50 value (gIC50; inhibitor concentration resulting in 50% growth inhibition) equal to 75 nM. I-BET726 modulates expression of genes involved in apoptosis, signaling, and MYC-family pathways. I-BET726 directly regulates expression of BCL2.