IC50: 5 nM ISRIB is a potent inhibitor of PERK signaling. As one of the four eIF2α kinases in mammalian cells, PERK responds to an accumulation of unfolded proteins in the endoplasmic reticulum. In vitro: Compared with cis-ISRIB, trans-ISRIB proved 100-fold more potent (IC50 = 5 nM vs IC50 = 600 nM), suggesting that ISRIB interacted with its cellular target stereospecifically. In addition, ISRIB could block the production of endogenous ATF4, while had no obvious effect on XBP1 mRNA splicing and XBP1s production. Meanwhile, ISRIB did not affect activation of the ATF6-branch of the UPR, however, ISRIB could block the downstream of PERK and eIF2α phosphorylation . In vivo: In mouse with a single intraperitoneal injection, ISRIB showed a plasma half-life of 8 hr and readily crossed the blood-brain barrier with quick equilibrium in the central nervous system. The detected brain ISRIB concentrations were found to be several fold higher than its IC50. Moreover, ISRIB-treated mice displayed significant enhancement in spatial and fear-associated learning. Therefore, memory consolidation was inherently limited by the ISR, and ISRIB could release suchbrake. These results showed that ISRIB might contribute to the understanding and treatment of cognitive disorders . Clinical trial: Up to now, ISRIB is still in the preclinical development stage.