GNE-617 hydrochloride |
| Catalog No.GC15967 |
NAMPT inhibitor, potent and competitive
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 2070014-99-0
Sample solution is provided at 25 µL, 10mM.
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GNE-617 hydrochloride is a potent and competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) with IC50 value of 5nM [1].
GNE-617 hydrochloride 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 hydrochloride shows the most optimal combination of in vitro metabolic stability, MDCK permeability and protein binding. Besides that, GNE-617 hydrochloride 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 hydrochloride also shows significant antitumor effects on U251 human glioblastoma tumor xenografts in mice and has no obvious effect on body weight loss [1, 2].
References:
[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.
Kinase experiment: | For RNA interference (RNAi), A549 cells are plated at 1,500 cells per well in 96-well plates, allowed to adhere for 24 hours, and transfected with 25 nM siRNA oligonucleotide using Dharmafect 4. Transfected cells are treated with the indicated concentrations of GNE-617 (0.1, 1 , 10 , 100 , and 1000 nM) for 72 hours and viability is evaluated with CellTiter-Glo. Lysates for detection of NAPRT1 protein are collected 72 hours after transfection of 1 million A549 cells in 10 cm dishes. For NAPRT1 re-expression, RERF-LC-MS cells are transfected with pCMV6-AC.NAPRT1 and empty vector pCMV6-AC using Amaxa Nucleofector technology and selected with Geneticin[1]. |
Cell experiment: | Cells are grown in RPMI-1640 medium supplemented with 10% FBS and 2 mM glutamine and passaged not more than 20 times after thawing. To determine the IC50 values and nicotinic acid rescue status, cells are treated with nine point dose titrations of GNE-617 with or without 10 μM nicotinic acid. At 96 hours post-drug addition, the GNE-617-treated cells are evaluated using CyQUANT Direct Cell Proliferation Assay followed by CellTiter-Glo Luminescent Cell Viability Assay quantified with a Wallac EnVision 2104 Multilabel Reader. IC50 values are calculated using XLfit 5.1. To examine the protein level, cells are lysed in ice-cold radioimmunoprecipitation assay buffer, run on SDS-PAGE (4%-12% Bis-Tris), and evaluated by Western blotting using antibodies directed against NAPRT1 and β-actin[1]. |
Animal experiment: | Rats[2] Male naïve Sprague Dawley rats are administered once daily (QD) via oral gavage either (1) GNE-617 at 30 mg/kg for 2 consecutive days in combination with NA at 75 mg/kg twice daily (BID; 6 h apart); (2) GNE-618 at 30 mg/kg for 1 day; or (3) GMX-1778 at 30 mg/kg for 1 day. Dose selection for each compound is based on tolerability and toxicity findings from the safety studies and for nicotinic acid (NA) on the highest concentration of NA that could be administered to rats in a solution form. Formulating NA at higher concentration resulted in a suspension, and NA is determined to be unstable in a suspension form. GNE-617, GNE-618, and GMX-1778 are formulated as a solution in the vehicle of 60% polyethylene glycol (PEG 400)/10% ethanol/30% 5% dextrose in water (D5W) (vol/vol/vol), and NA is formulated as a solution in water. At 1 h and 6.5 h post-dose (on Day 2 for GNE-617), rats (3-4 rats per time point) are euthanized, and the blood, retina, and brain are collected. Blood samples are collected into K2EDTA Microtainer tubes. The tubes are chilled on wet ice until centrifugation within 30 min of collection. Plasma is collected and transferred to 1.2 mL cluster tubes. Tissues are rinsed with phosphate-buffered saline and blotted dry using gauze. All samples are stored at more than −80°C until compound analysis. Results are expressed as an absolute concentration in retina, brain, or plasma and as a ratio of retina:plasma concentration. |
References: [1]. Shames DS, et al. Loss of NAPRT1 Expression by Tumor-specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors. Clin Cancer Res. 2013 Dec 15;19(24):6912-23. | |
| Cas No. | 2070014-99-0 | SDF | |
| Chemical Name | (Z)-N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carbimidic acid hydrochloride | ||
| Canonical SMILES | FC1=CC(F)=CC(S(C2=CC=C(C/N=C(O)/C3=CN4C=CN=C4C=C3)C=C2)(=O)=O)=C1.Cl | ||
| Formula | C21H16ClF2N3O3S | M.Wt | 463.88 |
| Solubility | Soluble in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1557 mL | 10.7786 mL | 21.5573 mL |
| 5 mM | 0.4311 mL | 2.1557 mL | 4.3115 mL |
| 10 mM | 0.2156 mL | 1.0779 mL | 2.1557 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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- Purity: >99.00%
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Average Rating: 5 (Based on Reviews and 35 reference(s) in Google Scholar.)
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