trans-ISRIB

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.

synonym(s): Integrated Stress Response inhibitor, trans-N,N′-(Cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide, trans-N,N′-1,4-Cyclohexanediylbis[2-(4-chlorophenoxy)-acetamide
Empirical Formula (Hill Notation):C22H24Cl2N2O4
CAS Number:1597403-47-8
Molecular Weight: 451.34

PROPERTIES
form
powder

color
white to beige

solubility
DMSO: 1 mg/mL, clear (warmed)

storage temp.
2-8°C

SMILES string
ClC1=CC=C(OCC(N[C@@H]2CC[C@@H](NC(COC3=CC=C(Cl)C=C3)=O)CC2)=O)C=C1

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)/t17-,18-

InChI key
HJGMCDHQPXTGAV-IYARVYRRSA-N

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.
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.

Application
ISRIB (integrated stress response inhibitor) has been used as an inhibitor of integrated stress response.

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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