GSK778 is a Potent and Selective Inhibitor of BET BD1
Posted On 2020-07-30
The bromodomain is a protein domain of about 110 amino acids, which can recognize acetylated lysine residues. Specifically, the bet (Bromo- and terminal domain) family consists of germ cell-specific (BRDT) and ubiquitously expressed (BRD2, BRD3, Brd4) epigenetic reader proteins. As a “reader” of lysine acetylation, bromodomain is responsible for transmitting signals carried by acetylated lysine residues and converting them into various normal or abnormal phenotypes. Besides, two tandem bromine domains of bet protein can bind chromatin to promote transcription. Moreover, drugs that also inhibit both bromine domains have shown efficacy in some malignant and inflammatory diseases. Furthermore, Bet protein is one of the most closely studied protein families in biology. Bet protein plays an important role in the regulation of normal development and the maintenance of oncogenes. GSK778 (iBET-BD1) is a potent and selective inhibitor of bromodomain (BRD) BD1.
GSK778 (iBET-BD1) is a potent and selective inhibitor of bromodomain (BRD) BD1.
But, how does GSK778 work on the target? Let’s discuss it in detail. First of all, GSK778 (iBET-BD1) is a potent and selective inhibitor of bromodomain (BRD) BD1. Meanwhile, GSK778 has IC50s of 75 nM (BRD2 BD1), 41 nM (BRD3 BD1), 41 nM (BRD4 BD1), and 143 nM (BRDT BD1), respectively.
In the second place, GSK778 inhibits BRD BD2 with the IC50s of 3950 nM (BRD2 BD2), 1210 nM (BRD3 BD2), 5843 nM (BRD4 BD2), and 17451 nM (BRDT BD2), respectively. Importantly, GSK778 inhibits the proliferative activity of human primary CD4+ T cells and the production of effector cytokines including IFNγ, IL-17A and IL-2. Particularly, GSK778 has a more pronounced effect on the growth and viability of MDA-453, MOLM-13, K562, MV4-11, THP-1, and MDA-MB-231 cells. Obviously, GSK778 reduces the clonogenic capacity of primary human AML cells
Last but not the least, GSK778 offers a superior survival advantage to iBET-BD2 in the aggressive MLL-AF9 AML model. Additionally, GSK778 reduces the production of anti-keyhole limpet hemocyanin (KLH) IgM and is well tolerated. In particular, GSK778 exhibits Cmax (85 ng/mL), Tmax (1.48 h) and AUC∞ (132 ng·h/mL) following oral administration (10 mg/kg) in mice.
All in all, GSK778 (iBET-BD1) is a potent and selective inhibitor of bromodomain (BRD) BD1.
Omer G, et, al. Science. 2020 Apr 24; 368(6489): 387-394.