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.
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.
ISRIB (integrated stress response inhibitor, 1597403-47-8) has been used as an inhibitor of integrated stress response.
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.
ISRIB, a drug that inhibits the integrated stress response (ISR), 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. This potent and selective inhibitor of ISR can penetrate the blood-brain barrier and prevent cells from adapting to the endoplasmic reticulum (ER) stress. By inhibiting the PERK signaling pathway, ISRIB can effectively reverse the effects of eIF2a phosphorylation and restore the cells' translation capacity, resulting in enhanced cognitive memory in rodents.
Trans-integrated stress response inhibitor is a small-molecule inhibitor of the cellular integrated stress response. The ISR is a coordinated collection of signaling pathways that activate different eukaryotic initiation factor 2 kinases to phosphorylate the subunit eIF2α. trans-ISRIB strongly reverses the effects of eIF2α phosphorylation in cells undergoing ISR. Phosphorylation of eIF2α stabilizes and inhibits turnover of the eIF2β protein complex. Both trans-ISRIB and eIF2(αP) bind to distinct sites within the guanine nucleotide exchange factor eIF2β. trans-ISRIB inhibits the ISR by promoting eIF2β nucleotide exchange activity and antagonizing the inhibitory effect of eIF2(αP) on eIF2β activity. Simultaneous binding of eIF2(αP) to eIF2β regulatory sites deforms the trans-ISRIB-binding pocket and prevents trans-ISRIB inhibition of the ISR. Because heightened ISR is sometimes associated with unfavorable outcomes, trans-ISRIB treatment can provide beneficial effects in models of neurodegeneration, chronic demyelination, and head injury.
[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.
