1597403-47-8

Basic information

• Product Name: ISRIB (trans-isoMer)
• Synonyms: ISRIB (trans-isoMer);trans-N,N'-(cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide);N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide) ISRIB(trans-isomer);Trans-ISRIB;Acetamide, N,N'-trans-1,4-cyclohexanediylbis[2-(4-chlorophenoxy)-
• CAS NO: 1597403-47-8
• Molecular Formula: C22H24Cl2N2O4
• Molecular Weight: 451.34296
• Product Categories: Inhibitors;API
• Mol File: 1597403-47-8.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 719.0±60.0 °C(Predicted)
• Appearance: /
• Density: 1.33±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: insoluble in EtOH; insoluble in H2O; insoluble in EtOH; ≥8.96 mg/mL in DMSO with gentle warming
• PKA: 13.63±0.40(Predicted)
• CAS DataBase Reference: ISRIB (trans-isoMer)(CAS DataBase Reference)
• NIST Chemistry Reference: ISRIB (trans-isoMer)(1597403-47-8)
• EPA Substance Registry System: ISRIB (trans-isoMer)(1597403-47-8)

Safety Data

• Hazardous Substances Data: 1597403-47-8(Hazardous Substances Data)

Usage

Description

ISRIB (trans-isomer), the trans-isomer of ISRIB, is a potent and selective PERK inhibitor with IC50 of 5 nM and does not have global effects on translation, transcription, or mRNA stability in non-stressed cells.

Uses

Different sources of media describe the Uses of 1597403-47-8 differently. You can refer to the following data:
1. trans-ISRIB is an 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. trans-ISRIB promotes survival of pluripotent stem cells in culture when used in combination with Chroman-1, emricasan, and polyamines, a combination known as CEPT. When used as part of the CEPT cocktail, trans-ISRIB improves survival of differentiated cells following cryopreservation. Brain penetrant.
2. ISRIB (integrated stress response inhibitor) has been used as an inhibitor of integrated stress response.

Biological Functions

ISRIB (trans-isomer) is a potent inhibitor of the integrated stress response (ISR).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).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. In stressed cells, ISRIB restored mRNA translation and inhibited stress granule (SG) formation induced by eIF2α phosphorylation. ISRIB inhibited the interaction between eIF2B and eIF2 that located at the core of the ISR. Also, ISRIB was an activator of eIF2B and stabilized activated eIF2B dimers.In mice, ISRIB significantly increased hippocampus-dependent spatial and fear-associated learning.

Biological Activity

ISRIB (integrated stress response inhibitor) as a drug, imparts resistance to the cells against the downstream effects of eukaryotic initiation factor 2 (eIF2)α phosphorylation such as activating transcription factor 4 (ATF4) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) induction.ISRIB is a blood- brain barrier penetrant, potent and selective inhibitor of integrated stress response (ISR) that impairs adaptation to ER stress. ISRIB is a potent inhibitor of PERK signaling, which potently reverses the effects of eIF2a phosphorylation and restores the cells translation capacity. ISRIB enhances cognitive memory in rodents.

Biochem/physiol Actions

ISRIB (integrated stress response inhibitor) as a drug, imparts resistance to the cells against the downstream effects of eukaryotic initiation factor 2 (eIF2)α phosphorylation such as activating transcription factor 4 (ATF4) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) induction.

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.

Upstream product

• 2615-25-0 trans-1,4-cyclohexyldiamine 
• 4122-68-3 4-chlorophenyloxyacetyl chloride 
• 15827-56-2 cis-1,4-cyclohexanediamine 

Relevant articles and documents

MODULATORS OF THE EIF2ALPHA PATHWAY

Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2 phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.