H3K27me3 is an epigenetic modification of DNA packaging protein histone H3. Specifically, it is a marker for the trimethylation of lysine 27 on histone H3 protein. Besides, H3K27me3 is relevant to the repair of DNA damage, especially the repair of double-strand breaks by homologous recombination. Moreover, H3k27me2 is widely in core histone H3 and plays a protective role by inhibiting non-cell specific enhancers. Furthermore, H3K27me3 plays an important role in maintaining gene repression during animal and plant development. Meanwhile, H3K27me3 inhibits a considerable number of developmental regulators or transcription factors.

For H3K27me3, histone markers can be erased by two demethylases belonging to the Jumonji C (JmjC) domain family. They are tetratricopeptide repeat (UTX, also known as KDM6A), Jumonji D3 (Jmjd3, also called KDM6B). Nonetheless, UTX and Jmjd3 shared 84% sequence similarity in their jmjc catalytic domain. Compared with other methylated histone lysine residues, they are specific for H3K27. Today, we will introduce a potent H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A dual inhibitor, GSK-J4.

GSK-J4 is a Dual Inhibitor of H3K27me3/me2-Demethylases JMJD3/KDM6B and UTX/KDM6A.

At first, GSK-J4 is a dual inhibitor of H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A with IC50s of 8.6 and 6.6 μM, respectively. Particularly, GSK-J4 inhibits LPS-induced TNF-α production in human primary macrophages with an IC50 of 9 μM. Obviously, GSK J4 is a cell-permeable prodrug of GSK-J1. GSK-J4 induces endoplasmic reticulum stress-related apoptosis.

Secondly, GSK-J4 has cellular activity in Flag-JMJD3-transfected HeLa cells. Administration of GSK-J4 increases totals nuclear H3K27me3 levels in untransfected cells. Interestingly, GSK-J4 significantly reduces the expression of 16 of 34 LPS-driven cytokines, including TNF-α. Interestingly, GSK-J4 with 5 μM for 48 hours causes a more than 3-fold increase in mouse podocyte H3K27me3 content. H3K27me3 levels in cultured podocytes, Additionally, GSK-J4 reduces Jagged-1 mRNA and Jagged-1 protein levels. GSK-J4 with 10-25 nM acts upon DCs promoting the differentiation of Treg cells, improving Treg stability and suppressive capacities. At the same time, GSK-J4 has no effect on the differentiation of Th1 and Th17 cells. GSK-J4 inhibits JMJD3 expression that is induced by TGF-β1.

Thirdly, GSK-J4 with 10 mg/kg by i.p. thrice-weekly for 10 weeks attenuates the development of kidney disease in diabetic mice. By the way, GSK-J4 significantly reduces the severity and delays the onset of the disease of the mouse model of experimental autoimmune encephalomyelitis.

All in all, GSK-J4 is a dual inhibitor of H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A.


Majumder S, et al. J Clin Invest. 2018 Jan 2;128(1):483-499.