The cell-permeable
trans diastereomer of a bis-glycolamide compound that acts as a potent and selective blocker of eIF2α/eIF2S1 Ser51 phosphorylation-initiated unfold protein response/UPR (Effec. conc. 25 to 200 nM in HEK293T, HeLa, MEF, U2OS cultures) upon ER stress induction. Although noncytotoxic in the absence of ER stress, ISRIB does cause enhanced apoptotic cell death upon ER stress induction by Thapsigargin/Tg (100 to 500 nM; Cat. Nos.
586005 &
586006) or Tunicamycin/Tm (2 to 5 µg/mL; Cat. No.
654380) treatment. Reported to exhibit good pharmacokinetics with blood-brain permeability in mice and significantly enhance learning and long-term memory in mice (0.25 mg/kg/d i.p.) and rats (25 ng/0.5 µL/275-350 g rat; amygdala administration via cannulation)
in vivo. Although the exact molecular target is not yet established, ISRIB most likely exerts its effect by modulating the interaction between the guanine nucleotide exchange factor eIF2B and the phosphorylated eIF2α (pS51).
The cell-permeable
trans-diastereomer of a
bis-glycolamide compound that acts as a potent and selective blocker ofeIF2α/eIF2S1-Ser51 phosphorylation-initiated unfold protein response/UPR (Effec. conc. 25 to 200 nM in HEK293T, HeLa, MEF, U2OS cultures) upon ER stress induction by Cys/Met starvation, HRI activation (6 µM KM09748), Thapsigargin/Tg (100 to 500 nM;
>Cat. Nos. 586005 & 586006) or Tunicamycin/Tm (2 to 5 µg/mL;
>Cat. No. 654380) treatment without affecting UPR responses independent of eIF2α (pS51), including ATF6 cleavage and IRE1-initiated XBP1s production. Although noncytotoxic in the absence of ER stress, ISRIB does prevent URP from properly restoring ER homeostasis following ER stress induction, causing enhanced apoptotic cell death in Tg- or Tm-treated HEK293T (2 µg/mL Tm & 200 nM ISRIB) and HeLa (25 nM ISRIB and 5 µg/mL Tm or 500 nM Tg) cultures. Reported to exhibit good pharmacokinetics with blood-brain permeability (plasma/brain
Tmax ≈ 6/6 h;
Cmax ≈ 180/100 ng/mL;
C24 h ≈ 55/33 ng/mL; 2.5 mg/kg i.p.) in mice and significantly enhance hippocampus-dependent learning of mice subjected to Morris water maze (0.25 mg/kg/d i.p.)
in vivo. Likewise, single amygdala administration via cannulation (25 ng/0.5 µL/275-350 g rat) immediately following auditory fear conditioning significantly enhances long-term, but not short-term, post-conditioning auditory response (% response above basal at 4 h/24 post conditioning = 27/33 vs. 27/22 among vehicle-treated control rats) in rats
in vivo. Although the exact molecular target is not yet established, ISRIB most likely exerts its effect by modulating the interaction between the guanine nucleotide exchange factor eIF2B and the phosphorylated eIF2α (pS51).
