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| Targets |
ISR-IN-2 targets the integrated stress response (ISR) pathway, a cellular signaling network activated by various stress conditions including endoplasmic reticulum stress, amino acid deprivation, and viral infection. The ISR pathway is mediated by the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which leads to global translation attenuation and selective translation of stress-responsive genes. By inhibiting the ISR, ISR-IN-2 blocks this stress response pathway with high potency (EC50 = 0.8 nM). The compound's mechanism of action involves binding to the ISR components and preventing the downstream effects of eIF2α phosphorylation.
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| ln Vitro |
In vitro studies have demonstrated that ISR-IN-2 is a potent inhibitor of the integrated stress response with an EC50 of 0.8 nM. The compound's inhibitory activity has been characterized in cell-based assays measuring the integrated stress response. Structure-activity studies of bis-O-arylglycolamides have been conducted to optimize its inhibitory potency. The compound has a purity of 98.21% to 99.22%. It is a white solid. These in vitro findings support its applications in studying cellular stress responses and related disease mechanisms.
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| ln Vivo |
In vivo studies of ISR-IN-2 are limited as the compound is primarily used as a research tool for in vitro and cellular studies. As a potent inhibitor of the integrated stress response, it may have potential for in vivo evaluation in models of neurodegenerative diseases, cancer, and other conditions where the ISR plays a role. However, comprehensive in vivo pharmacological studies specifically targeting ISR-IN-2 are not well documented in the available literature. The compound is intended for research use only and is not for human therapeutic use. Further research is needed to evaluate its in vivo efficacy and safety.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for ISR-IN-2 typically involve testing its inhibitory activity against the integrated stress response pathway. The compound's potency is assessed in cell-free or cell-based systems measuring ISR activation. EC50 values are determined from dose-response curves, with a reported EC50 of 0.8 nM. Structure-activity relationship studies have been performed to characterize the compound's binding and inhibitory properties. The compound's purity (≥98%) and identity are confirmed using analytical chemistry methods such as nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and mass spectrometry.
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| Cell Assay |
In vitro cell-based assays for ISR-IN-2 involve culturing cells to evaluate its inhibition of the integrated stress response. Cells are treated with varying concentrations of the compound and ISR activation is measured using reporter gene assays or by monitoring downstream markers of the stress response. The compound shows potent inhibition with an EC50 of 0.8 nM. Cell viability is assessed using standard assays to ensure that observed effects are not due to cytotoxicity. Structure-activity studies have been conducted to optimize the compound's inhibitory activity. All experiments are performed in triplicate with appropriate controls to ensure statistical reliability.
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| Animal Protocol |
In vivo animal experiments for ISR-IN-2 are not well documented in the available literature. As a research compound, it may be evaluated in animal models of neurodegenerative diseases, cancer, or other conditions where the integrated stress response plays a role. Animals would be administered the compound and disease progression monitored. Parameters assessed would include behavioral outcomes, biochemical markers, and histopathology. Control groups receiving vehicle alone would be included for comparison. All procedures would comply with institutional animal care and use committee guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of ISR-IN-2 reflect its nature as a small-molecule inhibitor. It has a molecular weight of 520.23 and the molecular formula C22H22Cl4N2O4. The compound has a LogP of 6.1, indicating high lipophilicity, and a topological polar surface area (tPSA) of 76.7. It has two hydrogen bond donors, four hydrogen bond acceptors, and eight rotatable bonds. The compound is typically a solid at room temperature. It is soluble in DMSO at 2.5 mg/mL (4.81 mM). It is stored as a powder at -20°C for up to 3 years and in solvent at -80°C for 6 months or -20°C for 1 month.
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| Toxicity/Toxicokinetics |
The toxicity profile of ISR-IN-2 has been evaluated in the context of its use as a research chemical. The compound has a purity of 98.21% to 99.22%. As a potent inhibitor of the integrated stress response, it may have biological effects that should be carefully evaluated. Proper handling procedures including use of personal protective equipment are recommended when working with the compound. The compound is not approved for human therapeutic use and is intended for research purposes only. Long-term toxicity studies would be needed to fully establish its safety profile for pharmaceutical applications.
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| References |
[1]. Hearn BR, et al. Structure-Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response. ChemMedChem. 2016 Apr 19;11(8):870-80.
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| Additional Infomation |
ISR-IN-2 (CAS# 1628478-12-5) is also known as Compound 47 and ISRIB-A15. It has the IUPAC name N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(2-(3,4-dichlorophenoxy)acetamide) and the chemical name 2-(3,4-dichlorophenoxy)-N-[4-[[2-(3,4-dichlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The compound is a potent inhibitor of the integrated stress response with an EC50 of 0.8 nM. Structure-activity studies of bis-O-arylglycolamides have been published. The compound is used in research applications for studying cellular stress responses, neurodegenerative diseases, and cancer. It is intended for research use only.
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| Molecular Formula |
C22H22CL4N2O4
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| Molecular Weight |
520.233082294464
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| Exact Mass |
520.03
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| CAS # |
1628478-12-5
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| PubChem CID |
90446750
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
6.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
569
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC(CCC1NC(=O)COC2=CC(=C(C=C2)Cl)Cl)NC(=O)COC3=CC(=C(C=C3)Cl)Cl
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| InChi Key |
JNLGSKLUABTOBY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H22Cl4N2O4/c23-17-7-5-15(9-19(17)25)31-11-21(29)27-13-1-2-14(4-3-13)28-22(30)12-32-16-6-8-18(24)20(26)10-16/h5-10,13-14H,1-4,11-12H2,(H,27,29)(H,28,30)
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| Chemical Name |
2-(3,4-dichlorophenoxy)-N-[4-[[2-(3,4-dichlorophenoxy)acetyl]amino]cyclohexyl]acetamide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 2.5 mg/mL (4.81 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9222 mL | 9.6111 mL | 19.2223 mL | |
| 5 mM | 0.3844 mL | 1.9222 mL | 3.8445 mL | |
| 10 mM | 0.1922 mL | 0.9611 mL | 1.9222 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.
Calculation results
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.
(2) Be sure to add the solvent(s) in order.
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