IOX1

IOX1 is a pan-inhibitor of 2-oxoglutarate-dependent demethylases and oxygenases.^1,2 It inhibits jumonji domain-containing 2C (JMJD2C), JMJD2E, JMJD1A, JMJD2A, jumonji AT-rich interactive domain 1C (JARID1C), and JMJD3 in cell-free assays (IC₅₀s = 0.6, 2.3, 1.8, 0.1, 19, and 1.4 µM, respectively) and inhibits demethylation of trimethylated lysine 9 on histone H3 (H3K9Me3) by JMJD2A in HeLa cells (IC₅₀ = 86.5 μM). IOX1 also inhibits the 2-oxoglutarate (2-OG) oxygenases hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2) and factor inhibiting HIF (FIH) with IC₅₀ values of 14.3 and 20.5 μM, respectively.² IOX1 (200 µM) reduces angiotensin Il-induced proliferation and migration of primary rat vascular smooth muscle cells (VSMCs).³ It is active against E. coli and A. baumannii in vitro and increases survival, decreases lung polymorphonuclear leukocytes (PMN) infiltration, and reduces serum and lung TNF-α, IL-1β, and IL-6 levels in a mouse model of LPS-induced endotoxemia when administered at a dose of 20 mg/kg.⁴ IOX1, alone and in combination with bevacizumab, decreases tumor weight and volume and increases intratumoral T cell infiltration in a CT26 murine model of colon cancer.⁵

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1. Schiller, R., Scozzafava, G., Tumber, A., et al. A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem 9(3), 566-571 (2014).

2. King, O.N.F., Li, X.S., Sakurai, M., et al. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS One 5(11), 1-12 (2010).

3. Hu, Q., Chen, J., Zhang, J., et al. IOX1, a JMJD2A inhibitor, suppresses the proliferation and migration of vascular smooth muscle cells induced by angiotensin II by regulating the expression of cell cycle-related proteins. Int. J. Mol. Med. 37(1), 189-196 (2016).

4. Lee, S.J., You, J.S., Gharbi, A., et al. IOX1 activity as sepsis therapy and an antibiotic against multidrug-resistant bacteria. Sci. Rep. 11(1), 2942 (2021).

5. Fang, S., Cao, H., Liu, J., et al. Antitumor effects of IOX1 combined with bevacizumab-induced apoptosis and immunity on colorectal cancer cells. Int. Immunopharmacol. 141, 112896 (2024).