ISRIB (trans-isomer)

Alias: ISRIB; trans-ISRIB
Cat No.:V0061 Purity: =99.07%
ISRIB, the trans-isomer of ISRIB, is a novel, potent and selective inhibitor of PERK (PRKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase) with IC50 of 5 nM.
ISRIB (trans-isomer) Chemical Structure CAS No.: 1597403-47-8
Product category: PERK
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of ISRIB (trans-isomer):

  • ISRIB (mixed cis- and trans-isomer)
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Purity & Quality Control Documentation

Purity: =99.07%

Purity: ≥98%

Product Description

ISRIB, the trans-isomer of ISRIB, is a novel, potent and selective inhibitor of PERK (PRKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase) with IC50 of 5 nM. With an IC50 value of 5 nM, ISRIB effectively counteracted the consequences of eIF2α phosphorylation. An endogenous transcription factor called ATF4 that binds to cAMP was inhibited by ISRIB. At the expense of polyribosomes brought on by endoplasmic reticulum (ER) stress, ISRIB in mouse embryonic fibroblasts (MEFs) reversed the rise in 80S monosomes. ER-stressed cells had lower cell survival when ISRIB was present. While inhibiting the formation of stress granules (SG) brought on by eIF2α phosphorylation in stressed cells, ISRIB also restored mRNA translation in these cells.

Biological Activity I Assay Protocols (From Reference)
Targets
PERK (IC50 = 5 nM)
ln Vitro

ISRIB blocks production of endogenous ATF4, whereas XBP1 mRNA splicing and XBP1s production persisted. By blocking signaling through the PERK branch of the UPR, ISRIB prevents cells from re-establishing ER homeostasis and reduces the viability of cells that are experiencing ER-stress.[1]

ln vivo
ISRIB exhibits positive characteristics in pharmacokinetic profiling experiments and good in vivo bioavailability. By improving spatial and fear-related learning, ISRIB (0.25 mg/kg i.p.) improves long-term memory in mice.[1]
Enzyme Assay
In 96-well plates, U2OS cells expressing the ATF4-dGFP-IRES-Cherry reporter are placed. For an 8-hour treatment, the cells are then exposed to 100 nM Thapsigargin and 10 M of the cherry-picked compounds. An automated microscope is used to visualize stained cells after Hoechst 33,258 staining. The INCell Developer Toolbox Software, version 1.9, is used to collect data and analyze images. Compounds that prevent the ATF4-dGFP reporter from being induced, do not prevent the buildup of mCherry downstream of the IRES, and are deemed non-toxic based on cell number measured by counting nuclei are purchased again for additional testing.
Cell Assay
On 96-well plates, U2OS cells are plated and given the night to recover. The level of eIF2α phosphorylation is measured after treatments with 2 µg/ml tunicamycin, 100 nM thapsigargin, 100 nM ISRIB in either the presence or absence of 100 nM ISRIB, or just ISRIB.
Animal Protocol
Mice: Female CD-1 mice that are 6-7 weeks old are given medication via the intra-peritoneal (ip) route. Groups of three mice/compound/route of administration receive a single dose of 5 mg/kg of animals. DMSO is used to dissolve ISRIB, which is then diluted 1:1 in super-refined PEG 400. Following dosing, blood (80 μL) is drawn from the saphenous vein in EDTA-containing collection tubes at intervals of 20 minutes, 1 hour, 3 hours, 8 hours, and 24 hours. Plasma is then prepared for analysis. Time-of-flight mass spectroscopy is used to find substances.
References

[1]. Elife. 2013 May 28;2:e00498.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H24CL2N2O4
Molecular Weight
451.344
Exact Mass
450.1113
Elemental Analysis
C, 58.55; H, 5.36; Cl, 15.71; N, 6.21; O, 14.18
CAS #
1597403-47-8
Appearance
Solid powder
SMILES
C1CC(CCC1NC(=O)COC2=CC=C(C=C2)Cl)NC(=O)COC3=CC=C(C=C3)Cl
InChi Key
HJGMCDHQPXTGAV-UHFFFAOYSA-N
InChi Code
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)
Chemical Name
2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide
Synonyms
ISRIB; trans-ISRIB
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~4 mg/mL (~8.89 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: <1 mg/mL
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.2156 mL 11.0781 mL 22.1562 mL
5 mM 0.4431 mL 2.2156 mL 4.4312 mL
10 mM 0.2216 mL 1.1078 mL 2.2156 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • ISRIB (trans-isomer)

    ISRIB (trans-isomer)Sidrauski C, et al. Elife. 2013, 2, e00498.
  • ISRIB (trans-isomer)

    ISRIB enhances spatial and fear-associated learning in rodents. Sidrauski C, et al. Elife. 2013, 2, e00498.
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