ISRIB (Integrated Stress Response InhiBitor) is a small molecule drug shown to restore memory function and cognitive impairments in mouse models for traumatic brain injury (TB) and Down Syndrome as well as enhance cognition in healthy and aged mice. ISRIB was also shown to be effective in animal models against noise-related hearing loss and prostate cancer. ISRIB was discovered in the lab of Peter Walter at University of California at San Francisco in 2013. It is a small molecule cognitive enhancer that interferes with integrated stress response (ISR). ISR functions as a safety mechanism that detects problems in protein production that could be a sign of viral infection or cancer and responds by putting on the brakes on cell protein synthesis. The process weeds out cells behaving abnormally but when the process is left on too long it can cause cells to lose their ability to perform normal activities. Chronic ISR activation is implicated in cognitive and behavioral deficits in patients after traumatic brain injury (TBI). Similar deficits occur in premature aging suggesting that ISR may underlie regular age-related cognitive decline as well. Age-induced maladaptive immune responses are also linked to ISR and markers for these were downregulated in aged mice treated with ISRIB.
ISRIB was identified in a screen of compounds for PERK inhibitor activity. PERK is an eIF2a kinase, one of the four eIF2α kinases that phosphorylate a unique serine in eIF2α. Kinases are enzymes that transfer a phosphate group to a molecule, a process called phosphorylation. Phophorylation of eIF2α is part of the collection of signaling pathways that comprise ISR, a process that occurs in distinct stress conditions such as viral infection, UV light or accumulation of unfolded proteins. ISR is conserved across multicellular animals. In the ISR process, the accumulation of unfolded proteins in the organelle called the endoplasmic reticulum causes activation of the protein kinase PERK. eIF2α is activated by PERK phosphorylation which reduces synthesis of most proteins. However certain mRNAs are preferentially translated or upregulated during ISR. eIF2α phosphorylation is implicated in memory consolidation. ISRIB was shown to reverse the effects of eIF2α phosphorylation. ISRIB does not block eIF2α phosphorylation but blocks downstream effects. ISRIB caused those cells subjected to PERK-activation by chronic endoplasmic reticulum stress to be less viable.
ISRIB is a symmetric bis-glycolamide containing a central bi-substituted cyclohexane. ISRIB can exist as two diastereomers. Interactions with the drug’s cellular target is stereospecific. Trans-ISRIB was 100-fold more potent than cis-ISRIB in their ability to inhibit an ATF4-luciferase reporter.
Calico, the Alphabet-owned biotechnology company purchased the license for ISRIB with aims to use the drug to treat dementia and Alzheimer’s.
