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Necrostatin-1

现货
Catalog No.
A4213
RIP1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 550.00
现货
10mg
¥ 450.00
现货
100mg
¥ 1,900.00
现货

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Background

IC50: Necrostatin-1 (Nec-1), (R)-5-([7-chloro-1H-indol-3-yl]methyl)-3-methylimidazolidine-2,4-dione (Nec-1a) (Figure 1A) (Degterev et al., 2008), exhibited an inhibitory constant (IC50) of 0.32 mM for RIP1 [1].

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Necrostatin-1, identified as a small-molecule inhibitor of necroptosis, is also a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1.

In vitro: Previous study indicated that necrostatin-1 was a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1 in vitro. In this study, RIP1 was found to be the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, two other necrostatins, necrostatin-3 and necrostatin-5, were also shown to target the RIP1 kinase step in the necroptosis pathway, but through different mechanism compared with that of necrostatin-1. The findings established necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis [2].

In vivo: A previous study was designed to investigate the protective effects and mechanisms of Nec-1 in concanavalin A-induced hepatitis in mice. It was found that in Nec-1-treated mice the amelioration in liver functions and histopathological changes and the suppression of inflammatory cytokine production were observed. Western blotting analyses showed that the expression of TNF-α, IFN-γ, IL2, IL6, and RIP1 was significantly reduced in the Nec-1-treated mice, which was further confirmed by immunofluorescence and immunohistochemistry. In addition, autophagosome formation was significantly reduced by Nec-1 treatment. These results indicated that Nec-1 could prevent concanavalin A -induced liver injury via RIP1-related and autophagy-related pathways [3].

Clinical trial: Up to now, Necroptosis is still in the preclinical development stage.

References:
[1] Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y.  Structural basis of RIP1 inhibition by necrostatins. Structure. 2013;21(3):493-9.
[2] Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J.  Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313-21.
[3] Yingqun Zhou, Weiqi Dai, Chunlei Lin, Fan Wang, Lei He, Miao Shen, Ping Chen, Chenfen Wang, Jie Lu, Ling Xu, Xuanfu Xu, and Chuanyong Guo.  Protective Effects of Necrostatin-1 against Concanavalin A-Induced Acute Hepatic Injury in Mice. Mediators of Inflammation. http://dx.doi.org/10.1155/2013/706156

文献引用

1. Ashok Kumar, Ramon Edwin Caballero, et al. "Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages." BioRxiv. 2019 February 06.
2. Luo Q, Yang D, et al. "Role of the Death Receptor and Endoplasmic Reticulum Stress Signaling Pathways in Polyphyllin I-Regulated Apoptosis of Human Hepatocellular Carcinoma HepG2 Cells." Biomed Res Int. 2018 Dec 25;2018:5241941. PMID:30671458
3. Yuan Z, Zhang H, et al. "A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation." Toxicology. 2019 Feb 15;414:45-56. PMID:30633930
4. Wang J, He H, et al. "Uncoupling effect of F16 is responsible for its mitochondrial toxicity and anti-cancer activity." Toxicol Sci. 2017 Oct 23. PMID:29069523
5. Chirieleison SM, Marsh RA, et al. "Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease." J Biol Chem. 2017 Apr 12. pii: jbc.M117.781500. PMID:28404814

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt259.33
Cas No.4311-88-0
FormulaC13H13N3OS
SynonymsMTH-DL-Tryptophan,Nec-1
Solubility≥12.97 mg/mL in DMSO, ≥13.29 mg/mL in EtOH with ultrasonic, <2.42 mg/mL in H2O
Chemical Name5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylideneimidazolidin-4-one
SDFDownload SDF
Canonical SMILESCN1C(=O)C(NC1=S)CC2=CNC3=CC=CC=C32
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

RIP1激酶检测

pcDNA3-FLAG-RIP1质粒转染293T细胞,RIP1激酶实验反应条件:10 μM预冷ATP、1 μCi [γ-32P]ATP在30℃进行30分钟。使用SDS-PAGE样品缓冲溶液煮沸样品终止反应,样品进行SDS-PAGE电泳,通过放射自显影可观察到RIP1带。

细胞实验 [2]:

细胞系

小鼠骨细胞系(MLO-Y4)

溶解方法

该化合物在DMSO中的溶解度> 10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应时间

30 mM; 24h

应用

Necrostatin-1 (30 mmol/L)可在体外抑制TNF-α诱导的小鼠骨细胞系(MLO-Y4)程序性坏死。

动物实验 [2, 3]:

动物模型

大鼠卵巢切除术;8周龄鼠做假手术或对照诱导AKI处理

剂量

1.65 mg/kg;腹腔注射给药;每日1次,持续4周

应用

Necrostatin-1 (1.65 mg/kg/d)显著地减少卵巢切除大鼠的RIP1、RIP3蛋白表达;同时,Necrostatin-1预防鼠渗透性肾病变的发生及对照诱导的AKI。

注意事项

请于室内测试所有化合物的溶解度。实际溶解度和理论值可能略有不同,这是由实验系统的误差引起的,属于正常现象。

References:

1. Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G., Hedrick, S. M., Gerber, S. A., Lugovskoy, A. and Yuan, J. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 4, 313-321

2. Cui, H., Zhu, Y., Yang, Q., Zhao, W., Zhang, S., Zhou, A. and Jiang, D. (2016) Necrostatin-1 treatment inhibits osteocyte necroptosis and trabecular deterioration in ovariectomized rats. Sci Rep. 6, 33803

3. Linkermann, A., Heller, J. O., Prokai, A., Weinberg, J. M., De Zen, F., Himmerkus, N., Szabo, A. J., Brasen, J. H., Kunzendorf, U. and Krautwald, S. (2013) The RIP1-kinase inhibitor necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice. J Am Soc Nephrol. 24, 1545-1557

生物活性

描述 Necrostatin-1是一种特异性的RIP1抑制剂,抑制TNF-α诱导的程序性坏死,EC50值为490 nM。
靶点 RIP1          
IC50 490 nM (EC50)          

质量控制

化学结构

Necrostatin-1

相关生物数据

Necrostatin-1

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Necrostatin-1

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Necrostatin-1

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Necrostatin-1