GMX1778 (CHS828)
(Synonyms: N-[6-(4-氯苯氧基)己基]-N'-氰基-N''-4-吡啶基胍,GMX1778) 目录号 : GC14815
GMX1778 (CHS828) 是一种特异性的烟酰胺磷酸核糖转移酶（NAMPT）抑制剂。
Cas No.:200484-11-3
Sample solution is provided at 25 µL, 10mM.
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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.
GMX1778 (CHS828) 是一种特异性的烟酰胺磷酸核糖转移酶（NAMPT）抑制剂[1]。NAD+（烟酰胺腺嘌呤二核苷酸）是一种存在于所有活细胞中的关键辅酶，在细胞能量代谢和氧化还原反应中发挥着重要作用[2]。GMX1778通过抑制NAMPT的活性，阻碍NAD+的生物合成，降低细胞内NAD+水平，进而引起ATP耗竭，最终诱导具有凋亡特征的程序性细胞死亡[3]。GMX1778通常用于癌症相关的研究[4]。
体外实验中，GMX1778（30nM-1µM；24小时）显著降低了HT1080细胞内的NAD⁺水平，并诱导了细胞毒性[5]。GMX1778（5nM；48小时）显著增加了NAPRT1阴性癌细胞（如U251和MDA-MB-231BR细胞）内的活性氧（ROS）水平，并导致细胞凋亡[6]。
体内实验中，GMX1778（100mg/kg/周；给药3周；口服灌胃）在神经内分泌肿瘤（NET）异种移植小鼠模型中显著增强了177Lu-DOTATATE治疗的抗肿瘤效果，延长了肿瘤进展的中位时间，并减少了肿瘤体积[7]。
| 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: | |
| Cas No. | 200484-11-3 | SDF | |
| 别名 | N-[6-(4-氯苯氧基)己基]-N'-氰基-N''-4-吡啶基胍,GMX1778 | ||
| 化学名 | (Z)-2-(6-(4-chlorophenoxy)hexyl)-1-cyano-3-(pyridin-4(1H)-ylidene)guanidine | ||
| Canonical SMILES | ClC1=CC=C(OCCCCCC/N=C(\N=C2C=CNC=C/2)NC#N)C=C1 | ||
| 分子式 | C19H22ClN5O | 分子量 | 371.86 |
| 溶解度 | ≥ 18.3mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6892 mL | 13.4459 mL | 26.8918 mL |
| 5 mM | 537.8 μL | 2.6892 mL | 5.3784 mL |
| 10 mM | 268.9 μL | 1.3446 mL | 2.6892 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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