| Description |
ISRIB (trans-isomer) is a potent inhibitor of PERK with an IC50 of 5 nM.
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| Related Catalog |
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| Target |
PERK:5 nM (IC50)
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| In Vitro |
Trans-ISRIB is 100-fold more potent (IC50=5 nM) than cis-ISRIB (IC50= 600 nM), indicating that the compound’s interaction with its cellular target is stereospecific. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress[1]. ISRIB substantially reverses the translational effects elicited by phosphorylation of eIF2α and induces no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation is blocked by ISRIB[2].
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| In Vivo |
ISRIB increases long-term memory in rodents. ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. ISRIB displays a half-life in plasma of 8 hr and readily crossed the blood-brain barrier, quickly equilibrating with the central nervous system[1].
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| Cell Assay |
U2OS cells are plated on 96-well plates and left to recover overnight. Cells are treated with either with 2 µg/ml tunicamycin or 100 nM thapsigargin in the presence or absence of 100 nM ISRIB or with ISRIB alone for the indicated and the level of eIF2α phosphorylation is determined[1].
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| Animal Admin |
Mice: Intra-peritoneal (ip) route of administration is performed on 6-7 wk old female CD-1 mice. Animals receives a single, 5 mg/kg dose in groups of three mice/compound/route of administration. ISRIB is dissolved in DMSO then diluted 1:1 in Super-Refined PEG 400. Blood (80 μL) is collected from the saphenous vein at intervals post-dosing (20 min, 1 hr, 3 hr, 8 hr, 24 hr) in EDTA containing collection tubes and plasma is prepared for analysis. Compounds are detected by time-of-flight mass spectroscopy[1].
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| References |
[1]. Sidrauski C, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498. [2]. Sidrauski C, et al. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stressgranule assembly. Elife. 2015 Feb 26;4. doi: 10.7554/eLife.05033.
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