| Description | Genz-123346 blocks the conversion of ceramide to glucosylceramide (GL1) and inhibits GM1 with an IC50 value of 14 nM. Genz-123346 is a potent, orally available glucosylceramide synthase inhibitor. |
| In vitro | In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 is primarily due to the effects on P-gp function. Genz-123346(Genz) is an enhancer of autophagy flux.Exposure of cells to Genz-123346 and to other GCS inhibitors at nontoxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents.?Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). |
| In vivo | In the Zucker diabetic fatty rat, Genz-123346 loared glucose and A1C levels and improved glucose tolerance.?Drug treatment also prevented the loss of pancreatic beta-cell function and preserved the ability of the animals to secrete insulin.?In the diet-induced obese mouse, treatment with Genz-123346 normalized A1C levels and improved glucose tolerance.?The oral bioavailability of the drug is shown to be about 10% and 30% in mice and rats, respectively, with a half-life in plasma of 30–60 min. Genz-123346 treatment results in a dose-dependent reduction of renal GlcCer and GM3 levels that translates into effective inhibition of cystic disease.?A direct effect of Genz-123346 on the Akt-mTOR signaling pathway is observed, with reduced phosphorylation of Akt and ribosomal protein S6.?A group of WT mice received Genz-123346 (0.11% final concentration in regular chow);?after 2 weeks of feeding, renal Gb3 was reduced by approximately 50%, in comparison with WT mice fed with chow diet only. |
| Target activity | GM1:14 nM |
| molecular weight | 987.23 |
| Molecular formula | C52H82N4O14 |
| CAS | 943344-58-9 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| References | 1. Zhao H, et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes. 2007 May;56(5):1210-8. 2. Chai L, et al. The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function. Int J Oncol. 2011 Mar;38(3):701-11. 3. Shen W, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014 Jun;129(5):884-94 4. Natoli TA, et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. 2010 Jul;16(7):788-92. 5. Morace I, et al. Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibitionprotects against acute kidney injury. Kidney Int. 2019 Aug;96(2):327-341. |