Ly93 is a selective sphingomyelin synthase 2 (SMS2) inhibitor with an IC50 of 91nM[1]. By inhibiting SMS2, Ly93 reduces sphingomyelin levels, thereby exerting anti-inflammatory and anti-atherosclerotic effects. Ly93 can be used in research related to atherosclerosis, dry eye disease, and epilepsy[2-3].
In vitro, Jurkat, Hut-102, and other T-cell malignancy cell lines were pretreated with Ly93 (10µM) for 1 hour, followed by treatment with compound V8 (4–6µM) for 6 hours. Ly93 attenuated V8-induced lysosomal membrane damage (reduction in Galectin-3-positive puncta) and decreased intracellular sphingomyelin levels[4]. NRK (normal rat kidney) cells were pretreated with Ly93 (35µM) for 30 minutes, followed by exposure to TcdB3 (0.2pM) for 4 hours. Ly93 blocked TcdB3-induced migrasome formation[5].
In vivo, high-fat diet-induced insulin-resistant C57BL/6 mice were treated with Ly93 (20-40mg/kg) via intragastric administration once daily for 12 weeks. Ly93 significantly improved insulin sensitivity[6]. In C57BL/6J mice, administration of Ly93 (100mg/kg) via gavage once daily for 7 days significantly reduced plasma sphingomyelin levels. Furthermore, apolipoprotein E knockout (apoE KO) mice on a Western diet were treated with Ly93 (12.5-40mg/kg) via gavage once daily for 7 weeks. Ly93 dose-dependently attenuated atherosclerotic lesions in both the aortic root and the entire aorta and reduced macrophage content within the lesions[7].
References:
[1] Hua F, Wang HR, Bai YF, et al. Substance P promotes epidural fibrosis via induction of type 2 macrophages. Neural Regen Res. 2023 Oct;18(10):2252-2259.
[2] Wan J, Hu Z, Zhu H, et al. The essential role of sphingolipids in TRPC5 ion channel localization and functionality within lipid rafts. Pharmacol Res. 2025 Mar;213:107648. doi: 10.1016/j.phrs.2025.107648. Epub 2025 Feb 7.
[3] Chen Q, Wei Y, Wang L, et al. Ly93 Inhibits Sphingomyelin Synthesis and Attenuates Inflammation and Injury in Dry Eye Conjunctival Organoids. Invest Ophthalmol Vis Sci. 2026 Feb 2;67(2):58.
[4] Qing Y, Guo Y, Zhao Q, et al. Targeting lysosomal HSP70 induces acid sphingomyelinase-mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies. Clin Transl Med. 2023 Mar;13(3):e1229.
[5] Li D, Yang Q, Luo J, et al. Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation. Cell Discov. 2024 Nov 5;10(1):112.
[6] Huang Y, Huang T, Zhen X, et al. A selective sphingomyelin synthase 2 inhibitor ameliorates diet induced insulin resistance via the IRS-1/Akt/GSK-3β signaling pathway. Pharmazie. 2019 Sep 1;74(9):553-558.
[7] Li Y, Huang T, Lou B, et al. Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor. Eur J Med Chem. 2019 Feb 1;163:864-882.
Ly93是一种选择性鞘磷脂合成酶2（SMS2；IC50=91nM）抑制剂[1]。Ly93通过抑制SMS2降低鞘磷脂水平，从而发挥抗炎、抗动脉粥样硬化等作用。Ly93可用于动脉粥样硬化、干眼症和癫痫的相关研究[2-3]。
在体外，Ly93（10µM）预处理Jurkat、Hut-102等T细胞恶性肿瘤细胞系1小时，随后以化合物V8（4–6µM）处理6小时。Ly93能够减弱V8诱导的溶酶体膜损伤，降低细胞内的鞘磷脂水平[4]。Ly93（35µM）预处理NRK（正常大鼠肾脏）细胞30分钟，随后以TcdB3（0.2pM）处理4小时，Ly93阻断了TcdB3诱导的迁移体形成[5]。
在体内，Ly93（20-40mg/kg）通过灌胃每天一次处理高脂饮食诱导的胰岛素抵抗C57BL/6小鼠，持续12周，显著改善了胰岛素敏感性[6]。Ly93（100mg/kg）通过灌胃每天一次处理C57BL/6J小鼠，持续7天，显著降低了血浆鞘磷脂水平。同时，Ly93（12.5-40mg/kg）通过灌胃每天一次处理apoE KO小鼠，持续7周。Ly93以剂量依赖性地减轻了主动脉根部和整个主动脉的动脉粥样硬化病变，并减少了病变中的巨噬细胞含量[7]。