GSK1210151A (I-BET151) is a novel BET bromodomain inhibitor which blocks recruitment of BET to chromatin. GSK1210151A exhibits potent selectivity over an extensive range of diverse protein types such as COX-2, P450, Aurora B, GSK3β, PI3K-γ, GPCR, ion channels and transporters. GSK1210151A displaces BRD3 and BRD4, PAFc and SEC components from chromatin resulting in inhibition of transcription at key genes (BCL2, C-MYC and CDK6) involved in the initiation of mixed lineage leukemia (MLL). GSK1210151A (I-BET151) induces apoptosis and G0/G1 cell cycle arrest in MLL-fusion leukemic cell lines in vitro with IC50 values of 15, 26, 120 and 192 nM for NOMO1, MV4;11, MOLM13 and RS4;11 cell lines respectively. GSK1210151A reduces BCL2 expression in NOMO1 cells. In vivo, GSK1210151A (I-BET151) improves survival and shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL|
|Source||Cell Stem Cell (2015). Figure 2. GSK1210151A|
|Method||Efficiently Generating CiNs|
|Cell Lines||TUJ1-stained cells|
|Incubation Time||14 days|
|Results||We found that an additional small molecule, I-BET151, dramatically enhanced the reprogramming rate (with a 90% TUJ1-positive cell yield) and neurite outgrowth of the iNs|
Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A).
Seal J, et al. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72. PMID: 22437115.
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
Dawson MA, et al. Nature. 2011 Oct 2;478(7370):529-33. PMID: 21964340.
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