| References: |
GSK1324726A (I-BET726) is a novel, potent, and selective small molecule inhibitor of BET proteins with high affinity to BRD2 (IC50= 41 nM), BRD3 (IC50= 31 nM), and BRD4 (IC50= 22 nM).in vitro: 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.
in vivo: I-BET726 was administered by oral gavage once daily at doses of 5 mg/kg or 15 mg/kg. Blood and tumor concentrations of I-BET726 were comparable between the two models, confirming that a similar exposure was achieved in the two studies. In the CHP-212 model, treatment with 5 mg/kg I-BET726 resulted in TGI equal to 50% (n=8; p= 0.1816), and mice in the 15 mg/kg group exhibited a TGI of 82% at the end of the study (n=5; p =0.0488). |
