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.