2,4-Pyridinedicarboxylic Acid (2,4-PDCA) is an inhibitor of histone lysine-specific demethylases that targets on JMJD2A (KDM4A), KDM4C, KDM4E (IC50, 1.4 μM), KDM5B (IC50, 3 μM), KDM6A and other 2-oxogynases [1][2].
Histone lysine-specific demethylases JMJD2A (KDM4A) and KDM4C are both members of the Jumonji domain 2 (JMJD2) family and function as trimethylation-specific demethylases, converting specific trimethylated histone residues to the dimethylated form. KDM5B is an H3K4me3⁄ me2-specific lysine demethylase [1][2].
2,4-Pyridinedicarboxylic Acid (2,4-PDCA) is an inhibitor of JMJD2A (KDM4A), KDM4C and KDM5B. In the FDH-coupled assay, 2,4-PDCA inhibited ccKDM5B with IC50 value of 3 ± 1 μM. In MALDI-TOF analysis of H3(1-21)K4me3, 2,4-PDCA reduced the level of H3(1-15) induced by ccKDM5B. In U2-OS cells transfected with KDM5B, 2,4-PDCA inhibited the decrease of H3K4me3 [1]. In HG-treated VSMCs, 2,4-PDCA (1.0 mM) inhibited JMJD2A and HG-induced proliferation in a concentration-dependent way, and inhibited HG-induced migration. 2,4-PDCA also reduced the mRNA and protein levels of MCP-1 and IL-6 [2].
In diabetic rats, 2,4-PDCA (7.5 mg/kg/d) reduced neointimal area and I/M ratio in the injured arteries 28 days after injury. 2,4-PDCA also inhibited the percentage of PCNA-positive cells in the neointima [2].
References:
[1]. Kristensen LH, Nielsen AL, Helgstrand C, et al. Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor. FEBS J, 2012, 279(11): 1905-1914.
[2]. Qi H, Jing Z, Xiaolin W, et al. Histone Demethylase JMJD2A Inhibition Attenuates Neointimal Hyperplasia in the Carotid Arteries of Balloon-Injured Diabetic Rats via Transcriptional Silencing: Inflammatory Gene Expression in Vascular Smooth Muscle Cells. Cell Physiol Biochem, 2015, 37(2): 719-734.