Description
GSK805 is a potent, orally bioavailable retinoid-related orphan receptor gamma t (RORγt) inverse agonist that interacts with the receptor''s putative ligand binding domain without exerting significant effects on DNA binding. It inhibits the expression of IL-17 (at 0.5 μM) in naïve CD4
+ T cells activated under Th17-cell-polarizing conditions and affects the broader RORγt-dependent gene network, inhibiting the development and pathogenic function of Th17 cells. GSK805 significantly reduces the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, when given orally to the hosts at 10 mg/kg daily beginning at the time of disease induction.
Uses
GSK805 is an orally active and CNS penetrant RORγt inhibitor. GSK805 inhibits RORγ and Th17 cells differentiation with pIC50 values of 8.4 and >8.2. GSK805 inhibits the function of Th17 cells. GSK805 can be used for the research of immunity[1].
in vivo
GSK805 (10 mg/kg; p.o. once per day for 35 days) improves the situation of mice with experimental autoimmune encephalomyelitis (EAE)[2].
GSK805 (30 mg/kg; p.o. once) inhibits Th17 cell responses in EAE mice[2].
| Animal Model: | C57BL/6 mice were immunized with MOG35–55 plus CFA[2] |
| Dosage: | 10 mg/kg |
| Administration: | Oral gavage; 10 mg/kg once per day; for 35 days |
| Result: | Efficiently ameliorated the severity of EAE in mice. |
| Animal Model: | C57BL/6 mice with EAE[2] |
| Dosage: | 30 mg/kg |
| Administration: | Oral gavage; 30 mg/kg once |
| Result: | Reduced both IFN-γ-IL-17+ and IFN-γ+IL-17+ T cells without altered the frequency of TNF-α+ T cells in EAE mice. |
References
[1] Wang Y, et al. Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors. ACS Med Chem Lett. 2015 May 26;6(7):787-792. DOI:
10.1021/acsmedchemlett.5b00122[2] Xiao S, et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity. 2014 Apr 17;40(4):477-89. DOI:
10.1016/j.immuni.2014.04.004
