GSK1210151A

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.