ISRIB (trans-isomer)PERK inhibitor,potent and selective CAS# 1597403-47-8 |
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Quality Control & MSDS
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| Cas No. | 1597403-47-8 | SDF | Download SDF |
| PubChem ID | 1011240 | Appearance | Powder |
| Formula | C22H24Cl2N2O4 | M.Wt | 451.34 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 38 mg/mL (84.19 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide | ||
| SMILES | C1CC(CCC1NC(=O)COC2=CC=C(C=C2)Cl)NC(=O)COC3=CC=C(C=C3)Cl | ||
| Standard InChIKey | HJGMCDHQPXTGAV-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C22H24Cl2N2O4/c23-15-1-9-19(10-2-15)29-13-21(27)25-17-5-7-18(8-6-17)26-22(28)14-30-20-11-3-16(24)4-12-20/h1-4,9-12,17-18H,5-8,13-14H2,(H,25,27)(H,26,28) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Integrated stress response (ISR) inhibitor; reverses the effects of eIF2α phosphorylation (IC50 = 5 nM) and restores cell translation capacity. Acts downstream of PERK, targeting interactions between eIF2α kinases and elF2B. Blocks ATF4 production without altering the IRE1 or ATF6 responses in vitro. Displays memory enhancement in hippocampus-dependent spatial and fear-associated learning in rodents. Brain penetrant. |
ISRIB (trans-isomer) Dilution Calculator
ISRIB (trans-isomer) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2156 mL | 11.0781 mL | 22.1562 mL | 44.3125 mL | 55.3906 mL |
| 5 mM | 0.4431 mL | 2.2156 mL | 4.4312 mL | 8.8625 mL | 11.0781 mL |
| 10 mM | 0.2216 mL | 1.1078 mL | 2.2156 mL | 4.4312 mL | 5.5391 mL |
| 50 mM | 0.0443 mL | 0.2216 mL | 0.4431 mL | 0.8862 mL | 1.1078 mL |
| 100 mM | 0.0222 mL | 0.1108 mL | 0.2216 mL | 0.4431 mL | 0.5539 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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.
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Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.[Pubmed:25858979]
Science. 2015 May 29;348(6238):1027-30.
The integrated stress response (ISR) modulates messenger RNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, we screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of guanine nucleotide exchange factor (GEF) eIF2B. When reintroduced by CRISPR-Cas9 gene editing of wild-type cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on eIF2B GEF activity toward its substrate, the translation initiation factor eIF2, in vitro. Thus, ISRIB targets an interaction between eIF2 and eIF2B that lies at the core of the ISR.
Pharmacological brake-release of mRNA translation enhances cognitive memory.[Pubmed:23741617]
Elife. 2013 May 28;2:e00498.
Phosphorylation of the alpha-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2alpha kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2alpha. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2alpha phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2alpha phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2alpha phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.
