GSK-J4 is a potent dual inhibitor of H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A with IC₅₀s of 8.6 and 6.6 μM, respectively. GSK-J4 inhibits LPS-induced TNF-α production in human primary macrophages with an IC₅₀ of 9 μM. GSK J4 is a cell permeable prodrug of GSK-J1^[1][2][3]. IC50 & Target: IC50: 8.6 µM (JMJD3/KDM6B), 6.6 µM (UTX/KDM6A)^[6] In Vitro: GSK-J4 has cellular activity in Flag-JMJD3-transfected HeLa cells, in which GSK-J4 prevents the JMJD3-induced loss of nuclear H3K27me3 immunostaining. Administration of GSK-J4 increases total nuclear H3K27me3 levels in untransfected cells. GSK-J4 significantly reduces the expression of 16 of 34 LPS-driven cytokines, including tumour-necrosis factor-α (TNF-α)^[1].
GSK-J4 (5 μM; 48 hours) causes a more than 3-fold increase in mouse podocyte H3K27me3 content. H3K27me3 levels in cultured podocytes, GSK-J4 reduces Jagged-1 mRNA and Jagged-1 protein levels. Correspondingly, when exposed podocytes to the inducer of dedifferentiation TGF-β1, pretreatment with GSK-J4 preventes both the increase in intracellular N1-ICD levels and the increase in α-SMA and the decrease in podocin mRNA levels^[2].
GSK-J4 (10, 25 nM) acts upon DCs promoting the differentiation of Treg cells, improving Treg stability and suppressive capacities, without affecting the differentiation of Th1 and Th17 cells^[3].
GSK-J4 inhibits JMJD3 expression that is induced by TGF-β1^[4].
GSK-J4 inhibits H3K4 demethylation at Xist, Nodal, and HoxC13 in female embryonic stem cells^[5]. In Vivo: GSK-J4 Hydrochloride (10 mg/kg; i.p.; thrice-weekly for 10 weeks) attenuates the development of kidney disease in diabetic mice^[2].
GSK-J4 (0.5 mg/kg, i.p.) significantly reduces the severity and delays the onset of the disease of the mouse model of experimental autoimmune encephalomyelitis^[3].