ONO-AE3-208 is a prostaglandin receptor (EP) 4-specific antagonist with Ki values of 1.3nM, 30nM, 790nM, and 2400nM for EP4, EP3, PGF, and thromboxane receptors, respectively[1]. By targeting EP4, ONO-AE3-208 inhibits blocks the levelsof IL-6 mRNA and IL-6 secretion, and interferes with the activity of the EP4-IL-6 axis pathway to inhibit cell adhesion and migration[2]. ONO-AE3-208 has been widely used in tumor research to reduce tumor metabolism and inhibit angiogenesis[3].
In vitro, ONO-AE3-208 treatment (10µM) for 24 hours significantly inhibited the migration of LNCaP cells, without affecting cell proliferation[4]. 100nM of ONO-AE3-208 pretreatment for 15 minutes attenuated the morphological changes induced by PGE2 in eosinophils and reversed the Ca2+ enhancement[5]. Treatment with 200nM ONO-AE3-208 for 24 hours reduced the activation of the NRLP3 inflammasome and the phosphorylation of NF-κB in the cultured rat peritoneal mesothelial cells (RPMCs)[6].
In vivo, ONO-AE3-208 treatment via oral administration at a dose of 0.5mg/kg/day for 4 weeks reduced angiotensin II infusion-induced abdominal aortic aneurysm formation and inhibited elastic fiber degradation in ApoE−/− mice[7]. Intraventricular injection of ONO-AE3-208 (10nmol) blocked Novokinin-induced anorexigenic activity and promoted food intake in mice that had been fasting for 18 hours within 60 minutes[8]. Oral administration of ONO-AE3-208 at a dose of 10mg/kg/day for 8 weeks alleviated renal injury, reduced proteinuria, and decreased mesangial matrix accumulation in diabetic mice[9].
References:[1] Xu S, Zhang Z, Ogawa O, et al. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer[J]. Cell biochemistry and biophysics, 2014, 70(1): 521-527.
[2] Fukae W, Ishikawa S, Iida Y, et al. EP4 stimulation promotes cell adhesion and migration via IL-6 signaling in oral squamous cell carcinoma[J]. The Journal of Physiological Sciences, 2026: 100057.
[3] Tokumasu M, Nishida M, Kawaguchi T, et al. Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model[J]. International Immunology, 2022, 34(6): 293-302.
[4] Xu S, Zhang Z, Ogawa O, et al. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer[J]. Cell biochemistry and biophysics, 2014, 70(1): 521-527.
[5] Luschnig-Schratl P, Sturm E M, Konya V, et al. EP4 receptor stimulation down-regulates human eosinophil function[J]. Cellular and Molecular Life Sciences, 2011, 68(21): 3573-3587.
[6] Luo Q, Liu M, Tan Y, et al. Blockade of prostaglandin E2 receptor 4 ameliorates peritoneal dialysis-associated peritoneal fibrosis[J]. Frontiers in Pharmacology, 2022, 13: 1004619.
[7] Yokoyama U, Ishiwata R, Jin M H, et al. Inhibition of EP4 signaling attenuates aortic aneurysm formation[J]. PloS one, 2012, 7(5): e36724.
[8] Ohinata K, Fujiwata Y, Shingo F, et al. Orally administered novokinin, an angiotensin AT2 receptor agonist, suppresses food intake via prostaglandin E2-dependent mechanism in mice[J]. Peptides, 2009, 30(6): 1105-1108.
[9] Thieme K, Majumder S, Brijmohan A S, et al. EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease[J]. Scientific Reports, 2017, 7(1): 3442.