SB 415286
(Synonyms: 3-[(3-氯-4-羟苯基)氨基]-4-(2-硝苯基)-1H-吡咯-2,5-二酮) 目录号 : GC13028
A selective inhibitor of GSK-3
Cas No.:264218-23-7
Sample solution is provided at 25 µL, 10mM.
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SB-415286 is a potent and selective cell permeable inhibitor of glycogen synthase kinase-3 (GSK-3) with Ki of 31 nM. It shows similar potency against GSK-3 and GSK3β [1].
SB-415286 inhibited GSK-3 activity and promoted glycogen synthesis in human liver cells and induced expression of reporter gene regulated by catenin-LEF/TCF in HEK293 cells [1]. In primary neurons, it can prevent cell death induced by repressed PI3k pathway activity [2]. Further studies showed that reduced GSK3β activity induced by SB-415286 could inhibit down-regulation of cyclin D1, cell cycle arrest and chemosensitivity, which were all mediated by rapamycin [3]. Pharmacologic inhibition of GSK-3β dramatically impaired p53-dependent transactivation of p21 and Puma but facilitated p53-dependent conformational activation of Bax, resulting in the conversion of p53-mediated damage response from cell cycle arrest to apoptosis [4]. SB-415286 reduced ischemia-reperfusion injury by mechanisms which were associated with mitochondria. SB-415286 reduced adenine nucleotide transport and phosphorylation of VDAC, then increased Bcl-2 binding to mitochondria and blocked opening of the mitochondrial permeability transition pore in cardiomyocytes [5]. SB-415286 had protective effect of hippocampal neurons on radiation-induced apoptosis as well. GSK-3β inhibition induced by SB-415286 could result in the upregulation of MDM2, which, in turn, regulated p53 degradation and p53-dependent cellular responses [6].
Recent research in a mouse model further confirmed that SB-415286 is a neuroprotectant against radiation-induced central nervous system necrosis. Mice treated with SB415286 prior to irradiation (i.e. a single 45-Gy fraction targeted to the left hemisphere), showed significant protection from radiation-induced necrosis, which was determined by in vivo MRI, in contrast with DMSO-treated mice [7].
References:
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000 Oct;7(10):793-803.
Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem. 2001 Apr;77(1):94-102.
Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res. 2005 Mar 1;65(5):1961-72.
Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res. 2005 Oct 1;65(19):9012-20.
Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res. 2008 Oct 24;103(9):983-91. doi: 10.1161/CIRCRESAHA.108.178970. Epub 2008 Sep 18.
Glycogen synthase kinase 3β inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2-p53 pathway. Cell Death Differ. 2012 Mar;19(3):387-96. doi: 10.1038/cdd.2011.94. Epub 2011 Jul 8.
A GSK-3β inhibitor protects against radiation necrosis in mouse brain. Int J Radiat Oncol Biol Phys. 2014 Jul 15;89(4):714-21. doi: 10.1016/j.ijrobp.2014.04.018.
Kinase experiment: | GSK-3 kinase activity is measured, in the presence or absence of SB-216763 or SB-415286, in a reaction mixture containing final concentrations of: 1 nM human GSK-3α or rabbit GSK3α; 50 mM MOPS pH 7.0; 0.2 mM EDTA; 10 mM Mg-acetate; 7.5 mM β-mercaptoethanol; 5% (w/v) glycerol; 0.01% (w/v) Tween-20; 10% (v/v) DMSO; 28 μM GS-2 peptide substrate. The GS-2 peptide sequence corresponds to a region of glycogen synthase that is phosphorylated by GSK-3. The assay is initiated by the addition of 0.34 μCi [33P]γ-ATP (IC50 determinations) or 2.7 μCi [33P]γ-ATP (Ki determinations). The total ATP concentration is 10 μM (IC50 determinations) or ranges from 0 to 45 μM (Ki determinations). Following 30 min incubation at room temperature the assay is stopped by the addition of one third assay volume of 2.5% (v/v) H3PO4 containing 21 mM ATP. Samples are spotted onto P30 phosphocellulose mats and these are washed six times in 0.5% (v/v) H3PO4. The filter mats are sealed into sample bags containing Wallac betaplate scintillation fluid. 33P incorporation into the substrate peptide is determined by counting the mats in a Wallac microbeta scintillation counter[1]. |
Cell experiment: | B65 cells are used after 24 h of in vitro culture. CGN are used after 7-8 days in vitro. Lithium and SB-415286 are dissolved in culture media and DMSO, respectively, and added to the neuronal preparation at the precise concentrations, 1 h before addition H2O2 (50 μM to 1 mM). To assess the loss in cell viability, we use the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium] method. MTT is added to the cells at a final concentration of 250 μM and incubated for 1 h, allowing the reduction in MTT to produce a dark blue formazan product. Media are then removed, and cells are dissolved in dimethylsulfoxide. Formazan production is measured by the absorbency change at 595 nm using a microplate reader. Viability results are expressed as percentages. The absorbency measured from non-treated cells is taken to be 100%[2]. |
References: [1]. Coghlan MP, et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000 Oct;7(10):793-803. | |
| Cas No. | 264218-23-7 | SDF | |
| 别名 | 3-[(3-氯-4-羟苯基)氨基]-4-(2-硝苯基)-1H-吡咯-2,5-二酮 | ||
| 化学名 | 3-(3-chloro-4-hydroxyanilino)-4-(2-nitrophenyl)pyrrole-2,5-dione | ||
| Canonical SMILES | C1=CC=C(C(=C1)C2=C(C(=O)NC2=O)NC3=CC(=C(C=C3)O)Cl)[N+](=O)[O-] | ||
| 分子式 | C16H10ClN3O5 | 分子量 | 359.73 |
| 溶解度 | ≥ 18mg/mL in DMSO, ≥ 44.9 mg/mL in EtOH with ultrasonic | 储存条件 | Store at RT |
| 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 | 2.7799 mL | 13.8993 mL | 27.7986 mL |
| 5 mM | 556 μL | 2.7799 mL | 5.5597 mL |
| 10 mM | 278 μL | 1.3899 mL | 2.7799 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet