Design and discovery of highly potent lysine 27 of histone H3 (H3K27) demethylase inhibitors for the treatment of inflammatory bowel disease.

Lysine specific demethylase 6A/B (KDM6A/B), histone lysine demethylases targeting H3K27me3, have emerged as key regulators of inflammatory gene expression and are increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). However, there remains a critical need for potent, selective, and cell-active KDM6A/B inhibitors to validate their therapeutic potential in inflammatory diseases like IBD. In this work, we conducted a systematic structure-activity relationship (SAR) study based on a lead compound GSK-J4 to improve its cellular inhibitory activity. Among these compounds, compound 39 suppressed H3K27me3 levels with an EC50 of 0.37 μM and a superior selectivity index (SICC50/EC50) of 25.27 against KDM6A/B in cells. Moreover, compound 39 showed high anti-inflammatory activity and significantly downregulated the expression levels of Il1b, Il6 and Tnfα in M1 macrophages. In a dextran sulfate sodium-induced murine colitis model, compound 39 significantly attenuated body weight loss and promoted recovery by reducing inflammatory macrophage populations. Thus, these findings demonstrate that the compound 39 is a promising novel candidate for the treatment of IBD.