A potent Nampt inhibitor
GNE-617 is a potent and competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) with IC50 value of 5nM [1].
GNE-617 is a potent inhibitor of NAMPT. It reduces the NAD levels in a > 95% reduction in both NAPRT1-deficient and NAPRT1-proficient cell lines and exerts EC50 values ranging from 0.54nM to 4.69nM. In the invitro ADME assessments, GNE-617 shows the most optimal combination of in vitro metabolic stability, MDCK permeability and protein binding. Besides that, GNE-617 has potent antiproliferation effects on various cell lines. The IC50 values of it in U251, HT1080, PC3, MiaPaCa2 and HCT116 cell lines are 1.8nM, 2.1nM, 2.7nM, 7.4nM and 2nM, respectively. Moreover, GNE-617 also shows significant antitumor effects on U251 human glioblastoma tumor xenografts in mice and has no obvious effect on body weight loss [1, 2].
参考文献:
[1] Zheng X, Bauer P, Baumeister T, et al. Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors. Journal of medicinal chemistry, 2013, 56(16): 6413-6433.
[2] O'Brien T, Oeh J, Xiao Y, et al. Supplementation of Nicotinic Acid with NAMPT Inhibitors Results in Loss of In Vivo Efficacy in NAPRT1-Deficient Tumor Models. Neoplasia, 2013, 15(12): 1314-IN3.
| Cell experiment [1]: | |
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Cell lines |
hARPE-19 and hRPEpC cell lines |
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Preparation method |
The solubility of this compound in DMSO is > 21.4 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.0032, 0.016, 0.08, 0.4, 2, and 10 μM, 3 d |
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Applications |
In rat retinal mixed cell population, cytotoxicity induced by GNE-617 is correlated with activity and potency. And human cells were more sensitive to cytotoxicity induced by GNE-617 than rat cells. |
| Animal experiment [2]: | |
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Animal models |
Female BALB/c SCID mice |
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Dosage form |
Oral administration, 5-30 mg/kg, twice daily for 5 days |
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Application |
When treated with GNE-617, a significant time-dependent decrease in NAD levels was observed in PC3 and HT-1080 xenograft tumors. In the HT-1080 xenograft model, GNE-617 decreased tumor NAD levels in a dose-dependent manner. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Zabka T S, Singh J T, Dhawan P, et al. Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase[J]. Toxicological Sciences, 2014: kfu268. [2]. O'Brien T, Oeh J, Xiao Y, et al. Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models[J]. Neoplasia, 2013, 15(12): 1314IN1-1329IN3. | |
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