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ISRIB

 
Catalog No.
B6093
PERK信号传导抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 545.00
现货
25mg
¥ 2,136.00
现货

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A

背景

IC50为5 nM。

ISRIB是PERK信号传导的强效抑制剂。

作为哺乳动物细胞中的四种eIF2α激酶之一,PERK应答内质网中未折叠蛋白的积累。

体外:已证实反式ISRIB比顺式ISRIB强效100倍(IC50 = 5 nM对比IC50 = 600 nM),表明ISRIB与其细胞靶点立体特异性相互作用。此外,ISRIB可以阻断内源性ATF4的产生,而对XBP1 mRNA剪接和XBP1的产生没有明显影响。同时,ISRIB不影响UPR的ATF6分支的活化,然而,ISRIB可阻断PERK下游和eIF2α磷酸化[1]。

体内:在单次腹膜内注射的小鼠中,ISRIB表现出8小时的血浆半衰期,并且容易穿过血脑屏障,在中枢神经系统中快速平衡。检测到的脑ISRIB浓度比其IC50高几倍。此外,ISRIB治疗小鼠表现出对空间和恐惧相关学习的显著增强。因此,记忆巩固必定受到ISR的限制,且ISRIB可以解除这种阻碍。这些结果表明,ISRIB可能有助于认知障碍的理解和治疗[1]。

临床试验:到目前为止,ISRIB仍处于临床前研究阶段。

参考文献:
[1] Sidrauski C, et al.  Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498.

文献引用

化学属性

Physical AppearanceA solid
StorageStore at -20°C
M.Wt451.34
Cas No.548470-11-7
FormulaC22H24Cl2N2O4
Solubilityinsoluble in H2O; insoluble in EtOH; ≥15.03 mg/mL in DMSO with gentle warming
Chemical Name(1Z,1'Z)-N',N''-((1r,4r)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetimidic acid)
SDFDownload SDF
Canonical SMILESClC1=CC=C(OC/C(O)=N/[C@@]2([H])CC[C@@](/N=C(O)/COC3=CC=C(Cl)C=C3)([H])CC2)C=C1
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试验操作

Cell experiment:[1]

Cell lines

HEK293T cells

Reaction Conditions

200 nM ISRIB for 24 h incubation

Applications

Addition of ISRIB alone did not affect cell viability, but caused a strong synergistic effect on ER-stressed cells, reducing colony number and size significantly more than ER-stress alone. This reduction in cell survival resulted from activation of apoptosis as the activity of the executioner caspases 3 and/or 7 was significantly induced under these conditions. Thus, ISRIB could synergize with ER stress to induce apoptosis.

Animal experiment:[1]

Animal models

Eight to ten-week-old male C57BL/6J mice

Dosage form

0.25 mg/kg

Injected intraperitoneally

Applications

In a Morris water maze, ISRIB-treated mice reached the hidden platform significantly faster compared to vehicle treated controls. The difference was already pronounced by days 3 and 4.

Note

The technical data provided above is for reference only.

References:

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

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