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ISRIB

Names

[ CAS No. ]:
1597403-47-8

[ Name ]:
ISRIB

[Synonym ]:
N,N'-1,4-Cyclohexanediylbis[2-(4-chlorophenoxy)acetamide]
Acetamide, N,N'-trans-1,4-cyclohexanediylbis[2-(4-chlorophenoxy)-
N,N'-trans-1,4-Cyclohexanediylbis[2-(4-chlorophenoxy)acetamide]
Acetamide, N,N'-1,4-cyclohexanediylbis[2-(4-chlorophenoxy)-
ISRIB
trans-ISRIB
ISRIB (trans-isomer)

Biological Activity

[Description]:

ISRIB (trans-isomer) is a potent inhibitor of PERK with an IC50 of 5 nM.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> PERK
Research Areas >> Neurological Disease

[Target]

PERK:5 nM (IC50)


[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].

[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].

[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].

[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].

[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.


[Related Small Molecules]

GSK2606414 | GSK2656157 | CCT020312

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
719.0±60.0 °C at 760 mmHg

[ Molecular Formula ]:
C22H24Cl2N2O4

[ Molecular Weight ]:
451.343

[ Flash Point ]:
388.6±32.9 °C

[ Exact Mass ]:
450.111328

[ PSA ]:
76.66000

[ LogP ]:
4.49

[ Appearance of Characters ]:
white solid

[ Vapour Pressure ]:
0.0±2.3 mmHg at 25°C

[ Index of Refraction ]:
1.603

[ Storage condition ]:
-20℃


Related Compounds

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