GLPBio

GMX1778 (CHS828)

Catalog No.: GC14815Purity:>99.00%Synonyms: GMX 1778
COASDSData Sheet

GMX1778 (CHS828) es un inhibidor competitivo de la nicotinamida fosforribosiltransferasa (NAMPT), con una IC50 menor a 25 nM. GMX1778 (CHS828) ejerce un efecto citotóxico al disminuir el nivel celular de NAD+ y exhibe una potente actividad anticancerígena.

Los productos son exclusivamente para uso en investigación. No aptos para uso humano. No vendemos a pacientes.

GMX1778 (CHS828)
Cas No.: 200484-11-3
10mM (in 1mL DMSO)In Stock
$38.00
1
5mgIn Stock
$34.00
1
10mgIn Stock
$55.00
1
25mgIn Stock
$116.00
1
50mgIn Stock
$186.00
1
100mgIn Stock
$297.00
1
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Descripción (Description)

GMX1778 (CHS828) is a specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT)[1]. NAD+ (Nicotinamide Adenine Dinucleotide) is a key coenzyme found in all living cells, playing an important role in cellular energy metabolism and redox reactions[2]. GMX1778 blocks the biosynthesis of NAD+ and decreases intracellular NAD+ levels by inhibiting the activity of NAMPT, which in turn causes ATP depletion and ultimately induces apoptosis-like programmed cell death[3]. GMX1778 is commonly used in cancer-related research[4].

In vitro, GMX1778 (30nM-1µM; 24h) significantly depleted intracellular NAD+ levels and induced cytotoxicity in HT1080 cells[5]. GMX1778 (5nM; 48h) significantly increased intracellular reactive oxygen species (ROS) levels and led to apoptosis in NAPRT1-negative cancer cells such as U251 and MDA-MB-231BR[6].

In vivo, GMX1778 (100mg/kg/week; 3 weeks; oral gavage) significantly enhanced the antitumor effect of 177Lu-DOTATATE treatment, prolonged the median time to tumor progression and reduced tumor volume in a neuroendocrine tumor (NET) xenograft mice model[7].

References:
[1] Watson M, Roulston A, Bélec L, et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol. 2009;29(21):5872-5888.
[2] Zapata-Perez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD+ homeostasis in human health and disease. EMBO Mol Med. 2021;13(7):e13943.
[3] Olesen UH, Christensen MK, Björkling F, et al. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem Biophys Res Commun. 2008;367(4):799-804.
[4] Ekelund S, Nygren P, Larsson R. Guanidino-containing drugs in cancer chemotherapy: biochemical and clinical pharmacology. Biochem Pharmacol. 2001;61(10):1183-1193.
[5] Guo J, Lam LT, Longenecker KL, et al. Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation. Biochem Biophys Res Commun. 2017;491(3):681-686.
[6] Cerna D, Li H, Flaherty S, Takebe N, Coleman CN, Yoo SS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778 regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53- and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner. J Biol Chem. 2012;287(26):22408-22417.
[7] Elf AK, Bernhardt P, Hofving T, et al. NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors. J Nucl Med. 2017;58(2):288-292.

Protocolo (Protocol)

Cell experiment [1]:

Cell lines

U251 and MDA-MB-231BR cells

Preparation Method

Human glioblastoma cell line (U251) were grown in RPMI 1640 media containing 2mM L-glutamine and 5% fetal bovine serum. MDA-MB-231 BR cells were grown in high glucose DMEM with 10% fetal bovine serum. Cultures were maintained at 37°C in an atmosphere of 5% CO2 and 95% room air. GMX1778 was reconstituted in DMSO (10mM) and stored at -80°C. Cells were seeded in 60mm2 plates and allowed to attach for 24h prior to 48h of exposure to GMX1778 (5nM). Superoxide levels were measured using the oxidation of the fluorescent dye, dihydroethidine (DHE). Apoptosis was measured using a Guava EasyCyte Plus.

Reaction Conditions

5nM; 48h

Applications

GMX1778 significantly increased intracellular reactive oxygen species (ROS) levels and led to apoptosis in NAPRT1-negative cancer cells such as U251 and MDA-MB-231BR.
Animal experiment [2]:

Animal models

female BALB/c nude mice

Preparation Method

The xenograft model with human small intestinal NET cell line GOT1 in nude mice was constructed by transplanted subcutaneously small pieces (about 1mm) of excised tumor to female BALB/c nude mice. GMX1778 was formulated as a 20mg/ml suspension in 2% carboxymethyl cellulose in 0.9% saline. Animals were divided into 4 groups; controls (vehicle only, n=6), 177Lu-DOTATATE (7.5MBq, n=10), GMX1778 (100mg/kg/week; 3 week; n=5), 177Lu-DOTATATE (7.5MBq) + GMX1778 (n=5). 177Lu-DOTATATE was injected in a tail vein and GMX1778 was given by oral gavage. In the combined therapy groups GMX1778 was given one hour after 177Lu-DOTATATE. Animals were followed up to 17 weeks and were killed when tumor weight exceeded 10% of body weight, or body weight was reduced by more than 10%. Animal weights and tumor sizes (longest diameter and the two perpendicular diameters measured by calipers) were monitored regularly. The relative tumor volume at a given time point was defined as the tumor volume divided by the volume at day 0.

Dosage form

100mg/kg/week; 3 weeks; oral gavage

Applications

GMX1778 significantly enhanced the antitumor effect of 177Lu-DOTATATE treatment, prolonged the median time to tumor progression and reduced tumor volume in a neuroendocrine tumor (NET) xenograft model.

References:
[1] Cerna D, Li H, Flaherty S, Takebe N, Coleman CN, Yoo SS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778 regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53- and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner. J Biol Chem. 2012;287(26):22408-22417.
[2] Elf AK, Bernhardt P, Hofving T, et al. NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors. J Nucl Med. 2017;58(2):288-292.

Documentos del producto (Product Documents)

Purity:>99.00%Appearance:A solid
COASDSData Sheet

Propiedades químicas (Chemical Properties)

N.º CAS
200484-11-3
Sinónimos
GMX 1778
Nombre químico
(Z)-2-(6-(4-chlorophenoxy)hexyl)-1-cyano-3-(pyridin-4(1H)-ylidene)guanidine
SMILES
ClC1=CC=C(OCCCCCC/N=C(\N=C2C=CNC=C/2)NC#N)C=C1
Fórmula molecular
C19H22ClN5O
Peso molecular
371.86
Solubilidad
≥ 18.3mg/mL in DMSO
Almacenamiento
Store at -20°C
Consejos generales
Seleccione un disolvente adecuado según los datos de solubilidad del producto. Una vez preparada, divida la solución madre en alícuotas para evitar ciclos repetidos de congelación y descongelación.
Utilice las soluciones madre en un plazo de 6 meses si se conservan a -80°C, o de 1 mes si se conservan a -20°C.
Para mejorar la solubilidad, caliente el tubo a 37°C y soníquelo durante un periodo adecuado.
Condiciones de envío
Las muestras de evaluación se envían con acumuladores de frío. Los demás tamaños se envían a temperatura ambiente o, previa solicitud, con acumuladores de frío.

Calculadoras (Calculators)Molaridad / Dilución / Peso molecular / Conversión de unidades / Formulación in vivo / Solubilidad

g/mol

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