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Sephin1

现货
Catalog No.
A8708
PPP1R15A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
50mg
¥ 1,250.00
现货

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Background

Sephin1 is a selective inhibitor of stress-induced PPP1R15A and targets disease associated with accumulation of misfolded protein. [1]
PPP1R15A is a regulator subunit of protein phosphatase 1 and regulates stress-induced eIF2α (α subunit of eukaryotic translation initiation factor 2). It brings PP1 (serine/threonine-protein phosphatase) to dephosphorylate eIF2α. Phosphorylation of eIF2α reduces protein synthesis and prevents the accumulation of misfolded protein in ER (endoplasmic reticulum). Thus inhibiting PPP1R15A prolongs the phosphorylation of eIF2α, and benefits the treatment for protein misfolding disease. [1]
In cells treated with 5μm Sephin1 for 6 hours, Sephin1 specifically disrupted the PPP1R15A-PP1c complex without affecting PPP115B-PP1c complex. As a consequence, Sephin1 prolonged eIF2a phosphorylation in HeLa cells after stress (*2.5 μg/ml tunicamycin treatment) and delayed translational recovery. Sephin1 recused cell from cytotoxic ER stress* in wild-type cell but not the PPP1R15A mutant cell. [1]
In mice administrated orally with 1-5mg/kg Sephin1 for given time, Sephin1 exhibited no adverse effects on rotarod performances, total body weight gain or memory. Treating MPZ (Deletion of serine 63 of myelin protein zero) mutant mice with 1mg/kg orally twice a day, prevented the molecular, morphological and motor defects. Oral treatment of 5 mg/kg of Sephin1 once a day, prevented motor deficits, motor neuron loss and the molecular defects in SOD1 (Mutant and misfolding-prone superoxide dismutase 1) mutant mice. [1]
Reference:
1: Das I, Krzyzosiak A, Schneider K, Wrabetz L, D'Antonio M, Barry N, Sigurdardottir A, Bertolotti A. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science. 2015 Apr 10; 348(6231):239-42.

文献引用

1. Chen Y, Podojil JR, et al. "Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis." Brain. 2019 Feb 1;142(2):344-361. PMID:30657878

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt196.64
Cas No.13098-73-2
FormulaC8H9ClN4
Solubility≥7.75mg/mL in DMSO
Chemical Name(E)-2-(2-chlorobenzylidene)hydrazinecarboximidamide
SDFDownload SDF
Canonical SMILESClC1=CC=CC=C1/C=N/NC(N)=N
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

细胞实验: [1]

细胞系

HeLa和293T细胞

制备方法

溶解度有限,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。

反应条件

6 h

实验结果

Sephin1选择性破坏PPP1R15A-PP1c复合物,但相关的PPP1R15B-PP1c复合物不受影响。Sephin1在应激后延长eIF2a磷酸化,延迟翻译恢复并减弱应激基因如促凋亡蛋白CHOP的表达。

动物实验: [1]

动物模型

SOD1小鼠;SOD1G93A突变C57BL/6J小鼠

给药剂量

5 mg/kg

实验结果

在SOD1突变小鼠中,5 mg/kg剂量的Sephin1每天一次给药,几乎完全阻止了渐进性体重减轻及其运动缺陷,而Sephin1对野生型小鼠的体重增加或运动功能没有不利影响。Sephin1还防止运动神经元损失相关的SOD1突变小鼠的运动缺陷。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

1. Das I, Krzyzosiak A, Schneider K et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science. 2015 Apr 10;348(6231):239-42.

质量控制

化学结构

Sephin1

相关生物数据

Sephin1