5.09584

ISR Inhibitor, ISRIB

• Synonym(e): ISR Inhibitor, ISRIB, trans-2-(4-Chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetylamino)cyclohexyl)acetamide, Integrated Stress Response Inhibitor, UPR Inhibitor, eIF2α (pS51) Signaling Inhibitor, eIF2S1 (pS51) Signaling Inhibitor, eIF2α (pS51) Signaling Inhibitor, eIF2S1 (pS51) Signaling Inhibitor, trans-2-(4-Chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetylamino)cyclohexyl)acetamide, Integrated Stress Response Inhibitor, UPR Inhibitor
• Empirische Formel (Hill-System): C₂₂H₂₄Cl₂N₂O₄
• CAS-Nummer: 1597403-47-8
• Molekulargewicht: 451.34
• MDL number: MFCD03403786
• UNSPSC Code: 12352200
• NACRES: NA.77
• PubChem Substance ID: 1011240
• Assay: ≥93% (HPLC)
• Form: powder
• Storage condition: OK to freeze, protect from light

Eigenschaften

• assay: ≥93% (HPLC)
• Quality Segment: 100
• form: powder
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze, protect from light
• color: light beige
• solubility: DMSO: 10 mg/mL
• storage temp.: 2-8°C
• SMILES string: C1CC(CCC1NC(=O)COC2=CC=C(C=C2)Cl)NC(=O)COC3=CC=C(C=C3)Cl
• InChI: 1S/C22H24Cl2N2O4/c23-15-1-9-19(10-2-15)29-13-21(27)25-17-5-7-18(8-6-17)26-22(28)14-30-20-11-3-16(24)4-12-20/h1-4,9-12,17-18H,5-8,13-14H2,(H,25,27)(H,26,28)
• InChI key: HJGMCDHQPXTGAV-UHFFFAOYSA-N

Beschreibung

General description

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; 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 T_max ≈ 6/6 h; C_max ≈ 180/100 ng/mL; C_{24 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).

Biochem/physiol Actions

Cell permeable: yes

Reversible: yes

Packaging

Packaged under inert gas

Preparation Note

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Other Notes

Sidrauski, C., et al. 2013 Elife2, e00498.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Disclaimer

Toxicity: Standard Handling (A)

Sicherheitshinweise

• Lagerklasse: 11 - Combustible Solids
• wgk: WGK 3
• flash_point_f: Not applicable
• flash_point_c: Not applicable