ISRIB (trans-isomer)
(Synonyms: ISRIB(TRANS-ISOMER)抑制剂) 目录号 : GC15462
An inhibitor of the Integrated Stress Response
Cas No.:1597403-47-8
Sample solution is provided at 25 µL, 10mM.
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.
| Cell experiment [1]: | |
|
Cell lines |
ER-stressed cells |
|
Preparation method |
The solubility of this compound in DMSO is >4.5 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
|
Reacting condition |
200 nM, 24 hr |
|
Applications |
ISRIB (trans-isomer) inhibited the ATF4-luciferase reporter with the IC50 of 5 nM. ISRIB (200 nM) blocked production of endogenous ATF4 in ER-stressed U2OS cells. ISRIB reduced the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. ISRIB (200 nM) sensitized HEK293T cells to acute ER stress. In Hela cells, ISRIB (25 nM) synergized with ER stress to activate caspase 3/7. In HEK293Trex cells carrying an inducible FLAG epitope-tagged ATF6, ATF6 cleavage was sustained in ER-stressed cells treated with ISRIB. |
| Animal experiment [1]: | |
|
Animal models |
Female CD-1 mice, male C57BL/6J mice |
|
Dosage form |
Intraperitoneal injection, 5 mg/kg |
|
Application |
ISRIB-treated mice displayed significant enhancement in spatial and fear-associated learning. In female CD-1 mice, ISRIB (5 mg/kg) displayed a half-life in plasma of 8 hr and readily crossed the blood-brain barrier, quickly equilibrating with the central nervous system. In male C57BL/6J mice, systemic administration of ISRIB (intraperitoneally, 2.5 mg/kg) enhanced long-term contextual fear memory. ISRIB enhanced auditory fear conditioning in male Sprague Dawley rats. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
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. |
|
| Cas No. | 1597403-47-8 | SDF | |
| 别名 | ISRIB(TRANS-ISOMER)抑制剂 | ||
| 化学名 | N,N'-((1s,4s)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide) | ||
| Canonical SMILES | C1CC(CCC1NC(=O)COC2=CC=C(C=C2)Cl)NC(=O)COC3=CC=C(C=C3)Cl | ||
| 分子式 | C22H24Cl2N2O4 | 分子量 | 451.34 |
| 溶解度 | ≥ 8.96 mg/mL in DMSO with gentle warming | 储存条件 | Store at -20°C |
| 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.2156 mL | 11.0781 mL | 22.1562 mL |
| 5 mM | 0.4431 mL | 2.2156 mL | 4.4312 mL |
| 10 mM | 0.2216 mL | 1.1078 mL | 2.2156 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: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet