Phosphorylation of eIF2α by several kinases in response to cellular stress, including accumulation of unfolded proteins in the ER, results in a decrease in overall protein synthesis but upregulation of a small number of key regulatory proteins. trans-ISRIB (Integrated Stress Response Inhibitor) is a symmetric bis-glycolamide that inhibits the eIF2α phosphorylation-mediated unfolded protein response following induction of ER stress (IC50 = 5 nM in a cell-reporter assay). Although the mechanism of action is not established, it does not directly inhibit phosphorylation of eIF2α by upstream kinases. trans-ISRIB is able to pass through the blood-brain barrier and significantly enhances learning and memory in mice and rats.
