Eliglustat is a specific, potent, orally active glucosylceramide synthase (GCS) inhibitor with IC50 of 24nM[1]. Eliglustat inhibits uridine diphosphate (UDP)-glucose ceramide glucosyltransferase-mediated glucose transfer from UDP-glucose to ceramide, thereby reducing glucosylceramide and downstream glycosphingolipid (GSL) synthesis and altering ceramide-dependent autophagy[1,4,5]. Eliglustat is used in research on Gaucher disease substrate accumulation, sphingolipid metabolism, insulin resistance, osteoclastogenesis, tumor-cell metabolism, myeloma bone disease, and Fabry disease substrate reduction[1-5].
In vitro, Eliglustat (0.6nM-1000nM; 72h) concentration-dependently reduced cell-surface ganglioside GM1 in K562 cells and ganglioside GM3 in B16/F10 melanoma cells, with mean IC50 values of 24nM and 29nM, respectively[1]. Eliglustat (128μM; 6h) increased intracellular ceramides and reduced GSLs in RM-9 and PC-3M prostate cancer cells, increased microtubule-associated protein 1 light chain 3 beta-II (LC3B-II), phosphatase and tensin homolog-induced kinase 1 (PINK1), and Parkin, and promoted mitochondrial fragmentation and lysosomal colocalization[4]. Eliglustat (0.1μM, 1μM, 10μM, 25μM, and 50μM; continuous exposure during 5-day culture with 50ng/mL macrophage colony-stimulating factor and 75ng/mL receptor activator of nuclear factor-κB ligand) concentration-dependently reduced tartrate-resistant acid phosphatase-positive osteoclast formation and multinucleation in RAW264.7 cells[5].
In vivo, Eliglustat (75mg/kg/day and 150mg/kg/day; oral gavage once daily for 10 weeks) dose-dependently reduced glucosylceramide accumulation and Gaucher-cell number in the liver, lung, and spleen of young D409V/null Gaucher mice[1]. Eliglustat (150mg/kg/day; oral intake in medicated chow ad libitum for 10 weeks) reduced lysosomal glucosylceramide in symptomatic D409V/null mice and limited renewed substrate accumulation following enzyme-mediated clearance[2]. Eliglustat (300mg/kg/day; oral intake in medicated chow ad libitum for 3-10 months) reduced plasma glucosylceramide and glucosylsphingosine and suppressed monoclonal paraprotein formation, lymphoma, and plasmacytoma development in inducible Gaucher mice[3]. Eliglustat (150mg/kg/day; oral intake in medicated chow ad libitum for 19 days) increased trabecular bone volume and trabecular number and reduced osteoclast indices in female C57BL/6J mice[5].
References:[1] McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, et al. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007;91(3):259-267. doi:10.1016/j.ymgme.2007.04.001.
[2] Marshall J, McEachern KA, Chuang WL, Hutto E, Siegel CS, Shayman JA, et al. Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy. J Inherit Metab Dis. 2010;33(3):281-289. doi:10.1007/s10545-010-9072-z.
[3] Pavlova EV, Archer J, Wang SZ, Dekker N, Aerts JM, Karlsson S, Cox TM. Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy. J Pathol. 2015;235(1):113-124. doi:10.1002/path.4452.
[4] Vykoukal J, Fahrmann JF, Gregg JR, Tang Z, Basourakos S, Irajizad E, et al. Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer. Nat Commun. 2020;11(1):4279. doi:10.1038/s41467-020-17645-z.
[5] Leng H, Zhang H, Li L, Zhang S, Wang Y, Chavda SJ, et al. Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease. Nat Commun. 2022;13(1):7868. doi:10.1038/s41467-022-35358-3.