IOX 1 is a potent broad‐spectrum inhibitor of 2OG oxygenases, which inhibits KDM4C, KDM4E, KDM2A, KDM3A and KDM6B with IC50 values of 0.6μM, 2.3μM, 1.8μM, 0.1μM and 1.4μM, respectively [1]. IOX 1 can increase the level of histone H3 methylation, inhibit the expression of matrix metalloproteinases, N-cadherin and vimentin, thereby suppressing the invasion of cancer cells [2]. IOX 1 has been widely used to reduce the proliferation of acute myeloid leukemia cells and regulate the DNA damage pathway [3].
In vitro, IOX 1 treatment for 2h (200μM) significantly inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by Ang II [4]. Treatment of N-WASP-deficient keratinocytes with 200μM IOX 1 for 24 hours can restore the expression of H3K9me2 and IL-23A [5]. Treatment with 100μM IOX 1 for 72 hours impaired proliferation of B cells in mouse spleens and suppressed cyclin E1 expression [6].
In vivo, IOX 1 treatment via intragastrical administration at a dose of 20mg/kg/day for 12 days reduced cardiomyocyte apoptosis and decreased the mRNA and protein expression levels of p53 and Bax in a mouse model of myocardial infarction (MI)[7].
References:
[1] Schiller R, Scozzafava G, Tumber A, et al. A cell‐permeable ester derivative of the JmjC histone demethylase inhibitor IOX1[J]. ChemMedChem, 2014, 9(3): 566-571.
[2] Chang S L Y, Lee C W, Yang C Y, et al. IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation[J]. Biochemical Pharmacology, 2023, 210: 115472.
[3] Monaghan L, Bunschoten R P, Bittencourt‐Silvestre J, et al. Selective small molecule targeting of KDM4 as a therapeutic strategy to reduce proliferation of acute myeloid leukaemia[J]. British Journal of Haematology, 2026.
[4] Hu Q I, 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[J]. International journal of molecular medicine, 2016, 37(1): 189-196.
[5] Li H, Yao Q, Mariscal A G, et al. Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation[J]. Nature communications, 2018, 9(1): 1420.
[6] Jiang Y, Li C, Wu Q, et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses[J]. Nature communications, 2019, 10(1): 2935.
[7] Shen C, Chen X, Lin Y, et al. Hypoxia triggers cardiomyocyte apoptosis via regulating the m6A methylation-mediated LncMIAT/miR-708-5p/p53 axis[J]. Heliyon, 2024, 10(11).