JTE 013 is a potent, orally available, and targeted S1P2 antagonist, with an IC50 value of 22±9nM for rat S1P2 [1]. JTE 013 inhibited the production of inflammatory cytokines and S1P, reduced monocyte chemotaxis, and inhibited RANKL-induced osteoclast precursor adhesion and fusion by targeting S1PR2[2]. JTE 013 has been widely used to regulate smooth muscle contraction and attenuate hypoxia-induced pulmonary hypertension in rodents[3].
In vitro, JTE 013 treatment for 72 hours significantly inhibited GH3 cell viability with an IC50 value of 41.17μM [4]. JTE 013 treatment for 3 hours markedly suppressed ceramide production in MV411 cells with an IC50 value of 16.6 ± 2.8µM[5]. Treatment with 10µM JTE 013 for 4h restored the lipopolysaccharide (LPS)-induced decrease in cell viability of human pulmonary microvascular endothelial cells (HPMECs), reduced inflammation levels, and abolished the inhibitory effect of LPS on junction protein levels in HPMECs[6].
In vivo, JTE 013 treatment via intraperitoneal injection (8mg/kg) once every other day for 5 days can reduce bleomycin-induced pulmonary fibrosis and inhibit the expression of RHOA/YAP pathway proteins in lung tissues of mice[7]. Treatment with JTE 013 at a dose of 2mg/kg via intraperitoneal injection every other day for 3 days in mice with bile duct ligation significantly reduced serum total bile acid levels and alleviated cholestatic liver injury[8].
References:
[1] Li M H, Swenson R, Harel M, et al. Antitumor activity of a novel sphingosine-1-phosphate 2 antagonist, AB1, in neuroblastoma[J]. The Journal of Pharmacology and Experimental Therapeutics, 2015, 354(3): 261-268.
[2] Yu H. Targeting S1PRs as a therapeutic strategy for inflammatory bone loss diseases—beyond regulating S1P signaling[J]. International Journal of Molecular Sciences, 2021, 22(9): 4411.
[3] Blankenbach K V, Schwalm S, Pfeilschifter J, et al. Sphingosine-1-phosphate receptor-2 antagonists: therapeutic potential and potential risks[J]. Frontiers in pharmacology, 2016, 7: 167.
[4] Sun H, Hu B, Wu C, et al. Targeting the SPHK1/S1P/S1PR2 axis ameliorates GH‐secreted pituitary adenoma progression[J]. European Journal of Clinical Investigation, 2024, 54(3): e14117.
[5] Pitman M R, Lewis A C, Davies L T, et al. The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism[J]. Scientific reports, 2022, 12(1): 454.
[6] Xu Q, Chen J, Zhu Y, et al. JTE-013 alleviates inflammatory injury and endothelial dysfunction induced by sepsis in vivo and in vitro[J]. Journal of Surgical Research, 2021, 265: 323-332.
[7] Zhou J, Song Y, Wang X, et al. JTE-013 alleviates pulmonary fibrosis by affecting the RhoA/YAP pathway and mitochondrial fusion/fission[J]. Pharmaceuticals, 2023, 16(10): 1444.
[8] Wang Y, Aoki H, Yang J, et al. The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice[J]. Hepatology, 2017, 65(6): 2005-2018.
JTE 013是一种强效、口服可用的靶向S1P2拮抗剂，对大鼠S1P2的IC50值为22±9nM[1]。JTE 013通过靶向S1PR2抑制炎性细胞因子和S1P的产生，减少单核细胞趋化，并抑制RANKL诱导的破骨细胞前体粘附和融合[2]。JTE 013已广泛用于调节平滑肌收缩和减轻啮齿动物缺氧诱导的肺动脉高压[3]。
在体外，JTE 013处理72小时以IC50值为41.17μM显著抑制了GH3细胞活力[4]。JTE 013处理3小时以IC50值为16.6±2.8µM显著抑制了MV411细胞中的神经酰胺生成[5]。用10µM的JTE 013处理4小时恢复了脂多糖（LPS）诱导的人肺微血管内皮细胞(HPMECs)活力下降，降低了炎症水平，并消除了LPS对HPMECs中连接蛋白水平的抑制作用[6]。
在体内，隔日腹腔注射JTE 013（8mg/kg）连续5天可减轻博来霉素诱导的肺纤维化，并抑制小鼠肺组织中RHOA/YAP通路蛋白的表达[7]。在胆管结扎小鼠中隔日腹腔注射2mg/kg剂量的JTE 013连续3天，显著降低了血清总胆汁酸水平并缓解了胆汁淤积性肝损伤[8]。