GSK046 (iBET-BD2)

GSK046 (iBET-BD2) is a selective and orally active inhibitor of BET, with IC50s of 264 nM (BRD2 BD2), 98 nM (BRD3 BD2), 49 nM (BRD4 BD2) and 214 nM (BRDT BD2), respectively[1].

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Epigenetics >> Epigenetic Reader Domain

BRD2 BD2:264 nM (IC50)

BRD3 BD2:98 nM (IC50)

BRD4 BD2:49 nM (IC50)

BRDT BD2:214 nM (IC50)

GSK046 (1000 nM; refresh every three days) reduces the recruitment of BET proteins to interferon (IFN) target genes following IFN-γ stimulation. GSK046 appears to more prominently affect the recruitment of BRD2 and BRD3 compared to BRD4[1]. GSK046 (0.1-10 μM) displays a more selective phenotypic fingerprint, particularly inhibiting the production of key pro-inflammatory mediators including Th17 cytokines in the B and T cell co-culture system[1]. GSK046 (0.01-10 μM; 72 hours) does not affect the proliferative activity of human primary CD4+ T cells but still inhibits the production of effector cytokines including IFNγ, IL-17A and IL-22[1]. GSK046 (0.005-10 μM; 48 hours) impairs macrophage activation following PMA stimulation, without impacting cellular viability[1]. Cell Proliferation Assay[1] Cell Line: Human primary CD4+ T cell Concentration: 0.001, 0.01, 0.1, 1, 10 μM Incubation Time: 72 hours Result: Did not affect the proliferative activity of the cells but still inhibited the production of effector cytokines.

GSK046 (40 mg/kg/QD; s.c. for 14 days) has immunomodulatory activity[1]. GSK046 exhibits Cmax (C57BL6 1589, C57B16 2993 ng/mL) and terminal elimination half-lives (C57BL6 1.8, C57B16 1.9 h) following oral administration (C57BL6 10, C57B16 40 mg/kg)[1]. GSK046 exhibits Cmax (mouse 1589, rat 202 ng/mL) and terminal elimination half-lives (mouse 1.8, rat 1.4 h) following oral administration (mouse 10, rat 10 mg/kg)[1]. Animal Model: Male C57BL/6 mice (8/10-weeks-old) are injected with keyhole limpet hemocyanin (KLH)[1] Dosage: 40 mg/kg/QD Administration: S.c. injections for 14 days Result: Reduced the production of anti-keyhole limpet hemocyanin (KLH) IgM and was well tolerated. Animal Model: Female C57BL/6 mice[1] Dosage: 10 mg/kg (Pharmacokinetic Analysis) Administration: Oral administration Result: Cmax (1859 ng/mL), T1/2 (1.8 h). Animal Model: Male C57BL/6 mice[1] Dosage: 40 mg/kg (Pharmacokinetic Analysis) Administration: Oral administration Result: Cmax (2993 ng/mL), T1/2 (1.9 h). Animal Model: Female Lewis rat[1] Dosage: 10 mg/kg (Pharmacokinetic Analysis) Administration: Oral administration Result: Cmax (202 ng/mL), T1/2 (1.4 h).

[1]. Omer G, et, al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020 Apr 24; 368(6489): 387-394.