Description
GSK J4 is a cell permeable prodrug rapidly hydrolyzed by macrophage esterases to GSK-J1, a potent selective jumonji H3K27 demethylase inhibitor. Jumonji C domain-containing histone demethylases (JHDMs) are Fe(II) and α-ketoglutarate dependent enzymes that oxygenate methylated histone lysine residues and thereby cause their demethylation. GSK-J1 is selective for the KDM6 subfamily members JMJD3 and UTX with an IC:50:of 60 nM in a JMJD3 assay, and is inactive against other demethylases of the JMJ family and over 100 tested kinases and histone deacetylases. The prodrug GSK-J4 inhibited TNF-α production with an IC:50:of 9 µM in LPS-stimulated human macrophages and blocked the production of TNF-α by macrophages derived from patients with rheumatoid arthritis. GSK J4 is an inhibitor of JMJD3 and UTX.GSK J4is A cell permeable inhibitor of the histone demethylase JMJD3/UTX