Sinbaglustat

Sinbaglustat (OGT2378) is a dual inhibitor of glucosylceramide synthase (GCS) and non-lysosomal glucosyl ceramidase (GBA2). Sinbaglustat is an orally available N-alkyl iminosugar that crosses the blood-brain barrier. Sinbaglustat can be used for the research of central neurodegenerative diseases associated with lysosomal dysfunctions[1][2].

Signaling Pathways >> Others >> Others

Research Areas >> Metabolic Disease

Sinbaglustat (OGT2378; 20 μM) reduces the synthesis of glucosylceramide and ganglioside by 93% and >95% in MEB4 melanoma cells compared with untreated MEB4 cells, respectively, without either cytotoxic or antiproliferative effects[1]. GBA2 is an enzyme involved in the catabolism of glycosphingolipids (GSLs). Sinbaglustat is 50-fold more potent in inhibiting GBA2 than GCS[2]. Cell Viability Assay[1] Cell Line: MEB4 murine melanoma cells Concentration: 2 or 20 μM Incubation Time: ≤96 hours Result: There was no demonstrable effect on cell proliferation, as measured by thymidine incorporation.

Sinbaglustat (OGT2378; administered p.o., in the powdered chow, at a dose of 2500 mg/kg/day, corresponding to 35-40 mg of Sinbaglustat per mouse per day) is highly effective in impeding melanoma tumor growth in vivo. The effectiveness of p.o. Sinbaglustat in this murine model suggests that inhibition of glycosphingolipid synthesis is a promising approach to inhibit tumor progression[1]. Animal Model: Female syngeneic C57BL/6 mice, 6-8 weeks old bearing MEB4 melanoma tumor[1] Dosage: 35-40 mg per mouse per day Administration: Administered p.o., in the powdered chow, at a dose of 2500 mg/kg/day Result: Inhibited MEB4 melanoma tumor growth in a syngeneic, orthotopic murine model.

[1]. Michael Weiss, et al. Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res. 2003 Jul 1;63(13):3654-8.

[2]. Martine Gehin, et al. Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders. Clin Transl Sci. 2021 Mar;14(2):558-567.