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I-BET151 (GSK1210151A) is a novel and selective inhibitor of the bromodomain and extra terminal (BET) family proteins BRD2, BRD3, and BRD4 with IC₅₀ of ~0.5 μM, 0.25 μM, and 0.79 μM respectively. It has profound effects on human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin.  In vivo studies indicate that I-BET151 can provide survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia.  I-BET151 is also an ApoA1 upregulator that was also found to mediate potent anti-inflammatory effects. It showed a broad anti-inflammatory profile in a LPS-challenged Balb/C mouse model.

How to Use:

• In vitro:  I-BET151 was used at 10 µM final concentration in various in vitro assays.
• In vivo: IP administration of I-BET151 at 30 mg/kg once per day was shown to provide survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Oral administration of I-BET151 at 10 mg/kg once per day in mice showed efficacy in acute inflammation mouse model.

Reference:

• 1.  Dawson MA, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. (2011) Nature. 478(7370):529-33. .
• 2.  Mirguet O, et al. From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151. (2012) Bioorg Med Chem Lett. 22(8):2963-7.
• 3.  Seal J, et al. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). (2012) Bioorg Med Chem Lett. 22(8):2968-72.