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Genz-123346
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Genz-123346
CAS No. : 943344-58-9
MCE 站:Genz-123346
产品活性:Genz-123346 是一种口服有效的葡萄糖神经酰胺合酶 (glucosylceramide synthase) 抑制剂。Genz-123346 阻断神经酰胺向葡萄糖神经酰胺 (GL1) 的转化,并抑制 GM1,IC50 值为 14 nM。
研究领域:Others
作用靶点:Others
In Vitro: 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. Genz-123346(Genz) is an enhancer of autophagy flux.
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.
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