The jumonji histone demethylases are essential components of transcriptional chromatin complexes. GSK-J4 HCl is a cell-permeable prodrug of GSK-J1, which selectively inhibits H3K27 demethylases JMJD3 and UTX with an IC50 value of 60nM. GSK-J4 at 25μM prevented JMJD3-induced loss of nuclear H3K27me3 immunostaining in Flag-JMJD3-transfected HeLa cells. GSK-J4 treatment also increased the total nuclear H3K27me3 level in non-transfected cells. GSK-J4 at 30μM inhibited LPS-induced inflammation in human primary macrophages derived from healthy volunteers. The IC50 value of GSK-J4 for inhibiting TNF-α protein production was 9μM. GSK-J4 at a concentration of 30μM prevented LPS-induced loss of H3K27me3 associated with the TNFA TSS[2]. In dextran sodium sulphate-treated mice, treatment with 1mg/kg GSK-J4 for 5 days reduced bodyweight loss and morbidity rate compared to the control group[3].
作用机制
GSK-J4 HCl is the ethyl ester derivative of GSK-J1, a selective inhibitor of H3K27 histone demethylase JMJD3 and UTX. GSK-J1 binds in the catalytic pocket of JMJD3. The bidentate interaction between the pyridyl-pyrimidine biaryl of GSK-J1 and the catalytic metal is critical for enzyme inhibition[1].
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