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ISRIB (trans-isomer)

现货
Catalog No.
B3699
有效的PERK选择性抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,190.00
现货
10mg
¥ 1,090.00
现货
25mg
¥ 2,190.00
现货

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Background

ISRIB (trans-isomer) is a potent inhibitor of the integrated stress response (ISR) [1].

Integrated stress response (ISR) is activated by diverse cellular conditions and rapidly reduces overall protein synthesis while enhancing translation of specific transcripts that support adaptive stress responses. The ISR is mediated by diverse stress-sensing kinases that phosphorylating serine 51 in eukaryotic translation initiation factor alpha (eIF2α) [2].

ISRIB (trans-isomer) is a potent ISR inhibitor. ISRIB reversed the effects of eIF2α phosphorylation with IC50 value of 5 nM. ISRIB inhibited production of endogenous ATF4 (a cAMP element binding transcription factor). In mouse embryonic fibroblasts (MEFs), ISRIB reversed the increase in the 80S monosomes at the expense of polyribosomes induced by endoplasmic reticulum (ER) stress. In ER-stressed cells, ISRIB reduced cell survival [1]. In stressed cells, ISRIB restored mRNA translation and inhibited stress granule (SG) formation induced by eIF2α phosphorylation [2]. ISRIB inhibited the interaction between eIF2B and eIF2 that located at the core of the ISR [3]. Also, ISRIB was an activator of eIF2B and stabilized activated eIF2B dimers [4].

In mice, ISRIB significantly increased hippocampus-dependent spatial and fear-associated learning [1].

References:
[1].  Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife, 2013, 2: e00498.
[2].  Sidrauski C, McGeachy AM, Ingolia NT, et al. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife, 2015, 4.
[3].  Sekine Y, Zyryanova A, Crespillo-Casado A, et al. Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science, 2015, 348(6238): 1027-1030.
[4].  Sidrauski C, Tsai JC, Kampmann M, et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife, 2015, 4: e07314.

文献引用

1. Hongbo Zhang, Clarissa Read, et al. "A cytomegalovirus immunevasin triggers integrated stress 1 response-dependent reorganization of the endoplasmic reticulum." bioRxiv. 2019 May 17.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt451.34
Cas No.1597403-47-8
FormulaC22H24Cl2N2O4
Solubility≥8.96 mg/mL in DMSO with gentle warming
Chemical NameN,N'-((1s,4s)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide)
SDFDownload SDF
Canonical SMILESC1CC(CCC1NC(=O)COC2=CC=C(C=C2)Cl)NC(=O)COC3=CC=C(C=C3)Cl
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

ER应激细胞

溶解方法

该化合物在DMSO中的溶解度大于4.5 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

200 nM,24小时

应用

ISRIB反式异构体抑制ATF4-荧光素酶报告基因,IC50为5 nM。ISRIB(200 nM)阻断ER应激U2OS细胞中内源性ATF4的生成。ISRIB通过慢性内质网应激降低了PERK激活的细胞活力。ISRIB(200 nM)使HEK293T细胞对急性ER应激敏感。在Hela细胞中,ISRIB(25 nM)与ER应激协同作用激活caspase 3/7。在携带可诱导的FLAG表位标记ATF6的HEK293Trex细胞中,ISRIB处理的ER应激细胞中维持ATF6切割。

动物实验[1]:

动物模型

雌性CD-1小鼠,雄性C57BL/6J小鼠

给药剂量

腹腔注射,5 mg/kg

应用

在小鼠中,ISRIB治疗显著增强空间和恐惧相关学习。在雌性CD-1小鼠中,ISRIB(5 mg/kg)的血浆半衰期为8小时,并且容易地穿过血脑屏障,与中枢神经系统快速平衡。在雄性C57BL/6J小鼠中,腹腔给药2.5 mg/kg 剂量的ISRIB增强了长期的语境恐惧记忆。ISRIB增强了雄性Sprague Dawley大鼠的听觉恐惧条件。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory[J]. Elife, 2013, 2: e00498.

生物活性

Description ISRIB (trans-isomer),ISRIB的反式异构体,是有效的PERK选择性抑制剂,其IC50值为5 nM。
靶点 PERK          
IC50 5 nM          

质量控制

化学结构

ISRIB (trans-isomer)

相关生物数据

ISRIB (trans-isomer)