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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].

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