Genz-123346 

Genz-123346 is a potent, orally available glucosylceramide synthase inhibitor. Genz-123346 blocks the conversion of ceramide to glucosylceramide (GL1) and inhibits GM1 with an IC₅₀ value of 14 nM^[1].

IC50: 14 nM (GM1)^[1]

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 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^[2]. Genz-123346(Genz) is an enhancer of autophagy flux^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

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^[1].
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^[4].
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^[5].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

987.23

C₅₂H₈₂N₄O₁₄

943344-58-9

CCCCCCCCC(N[C@H](CN1CCCC1)[C@@H](C2=CC=C(OCCO3)C3=C2)O)=O.CCCCCCCCC(N[C@H](CN4CCCC4)[C@@H](C5=CC=C(OCCO6)C6=C5)O)=O.O=C(O)[C@H](O)[C@@H](O)C(O)=O

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [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.  [Content Brief]

  [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.  [Content Brief]

  [3]. Shen W, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014 Jun;129(5):884-94  [Content Brief]

  [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.  [Content Brief]

  [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.  [Content Brief]