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| Targets |
The primary target of eIF4A3-IN-2 is eukaryotic initiation factor 4A-3 (eIF4A3), an ATP-dependent RNA helicase that is a core component of the exon junction complex (EJC). eIF4A3 plays critical roles in RNA splicing, translation initiation, and nonsense-mediated mRNA decay (NMD). eIF4A3-IN-2 acts as a selective, noncompetitive inhibitor that binds to the allosteric region of eIF4A3 with an IC₅0 of 110 nM. By inhibiting eIF4A3, the compound disrupts EJC formation and function, affecting RNA processing and gene expression. eIF4A3 is a validated target for cancer research and other diseases driven by aberrant RNA metabolism.
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| ln Vitro |
eIF4A3-IN-2 (Compound 2) binds to the allosteric region of eIF4A3 and, in vitro, inhibits the activities of ATPase, helicase, and cellular nonsense-mediated RNA decay (NMD) [1].
In vitro studies demonstrate that eIF4A3-IN-2 is a highly selective and noncompetitive inhibitor of eIF4A3 with an IC₅0 of 110 nM. The compound binds to the allosteric region of eIF4A3, providing specificity and avoiding competition with ATP. This mechanism of inhibition makes eIF4A3-IN-2 a valuable tool for studying the biological functions of eIF4A3, including its roles in RNA splicing, translation, and nonsense-mediated mRNA decay. The compound's selectivity for eIF4A3 over other helicases and its noncompetitive mode of action are key features of its activity profile. |
| ln Vivo |
In vivo studies of eIF4A3-IN-2 are limited, as it is primarily used as a research tool in cellular assays. However, given its potent and selective inhibition of eIF4A3 with an IC₅0 of 110 nM, the compound may have potential for in vivo efficacy studies in animal models of diseases where eIF4A3 plays a role, such as cancer. eIF4A3 is involved in RNA splicing and translation, processes that are often dysregulated in cancer. Further studies are needed to evaluate its pharmacokinetic properties, bioavailability, and efficacy in vivo. The compound may also be useful for studying the role of eIF4A3 in other physiological processes.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, eIF4A3-IN-2 is evaluated using helicase activity assays that measure the ATP-dependent RNA unwinding by eIF4A3. The compound is incubated with recombinant eIF4A3 protein, RNA substrate, and ATP at various concentrations. eIF4A3-mediated RNA unwinding is quantified using fluorescence-based or gel-based methods. IC₅0 values are determined from dose-response curves. Binding affinity to the allosteric region can be assessed using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). Selectivity profiling against other helicases may be performed to confirm specificity.
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| Cell Assay |
Apoptosis analysis [1]
Cell Types: HEK293T cells (transfected with NMD reporter gene) Luciferase assay Tested Concentrations: 0.3, 1, 3 or 10 μM Incubation Duration: 3 or 6 hrs (hours) Experimental Results: eIF4A3-IN-2 induces apoptosis The luciferase activity increased approximately 3.2 times, indicating that NMD was inhibited by compound 2[1]. For in vitro cellular experiments, eIF4A3-IN-2 is tested in cell lines to evaluate its effects on eIF4A3 function and downstream RNA processing. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from nanomolar to micromolar). eIF4A3 inhibition is assessed by measuring its effects on RNA splicing, translation, or nonsense-mediated mRNA decay (NMD). Gene expression changes are analyzed by qPCR or RNA sequencing. Cell viability and proliferation are monitored using standard assays. The compound's effects on EJC formation can be assessed using RNA immunoprecipitation or other methods. |
| Animal Protocol |
For in vivo animal experiments, eIF4A3-IN-2 can be administered to animals via various routes including oral gavage, intravenous injection, or intraperitoneal injection, depending on its solubility and pharmacokinetic properties. The compound's efficacy can be evaluated in tumor models or other disease models where eIF4A3 plays a role. Typical dosing regimens may range from 1 to 50 mg/kg administered daily or intermittently. Pharmacodynamic markers such as RNA splicing changes or NMD inhibition are measured in tissues. Tumor volume, body weight, and overall health are monitored.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of eIF4A3-IN-2 are not extensively detailed in the public literature. As a small molecule with a molecular weight of 602.7 g/mol, it may have reasonable oral bioavailability and tissue distribution. The presence of bromine and chlorine atoms may influence its metabolic stability and clearance. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies. The compound's protein binding, metabolism, and excretion pathways remain to be fully characterized. Formulation development may be necessary for optimal in vivo administration.
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| Toxicity/Toxicokinetics |
Toxicological data for eIF4A3-IN-2 are limited, as it is primarily a research tool. As an eIF4A3 inhibitor, its toxicity would depend on the importance of eIF4A3 for normal cellular function. eIF4A3 is a core component of the exon junction complex and plays critical roles in RNA splicing and translation. Its inhibition could have significant effects on gene expression and cell function. Comprehensive toxicology studies would be needed for further development. Appropriate safety precautions should be taken when handling this compound, including the use of personal protective equipment and adherence to institutional safety guidelines.
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| References | |
| Additional Infomation |
eIF4A3-IN-2 is a research compound used to study eIF4A3 biology and RNA processing. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound is a highly selective and noncompetitive eIF4A3 inhibitor with an IC₅0 of 110 nM that binds to the allosteric region of eIF4A3. It is a valuable tool for exploring RNA-binding protein function, post-transcriptional control mechanisms, and potential therapeutic strategies in cancer and other diseases driven by aberrant RNA metabolism.
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| Molecular Formula |
C25H19BR2CLN4O2
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| Molecular Weight |
602.704962968826
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| Exact Mass |
601.954
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| CAS # |
2095677-20-4
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| Related CAS # |
(R)-eIF4A3-IN-2;2095484-82-3
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| PubChem CID |
131953885
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| Appearance |
White to light yellow solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
34
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| Complexity |
744
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| Defined Atom Stereocenter Count |
1
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| SMILES |
BrC1C=CC2=C(C=NN2C=1)C(N1CCN(C(C2C=CC(=CC=2)Br)=O)[C@@H](C2C=CC(=CC=2)Cl)C1)=O
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| InChi Key |
WKKAVTNXNVPCCN-HSZRJFAPSA-N
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| InChi Code |
InChI=1S/C25H19Br2ClN4O2/c26-18-5-1-17(2-6-18)24(33)31-12-11-30(15-23(31)16-3-8-20(28)9-4-16)25(34)21-13-29-32-14-19(27)7-10-22(21)32/h1-10,13-14,23H,11-12,15H2/t23-/m1/s1
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| Chemical Name |
(4-bromophenyl)-[(2S)-4-(6-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]methanone
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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 : ~100 mg/mL (~165.92 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.15 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (2.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.67 mg/mL (2.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6592 mL | 8.2959 mL | 16.5917 mL | |
| 5 mM | 0.3318 mL | 1.6592 mL | 3.3183 mL | |
| 10 mM | 0.1659 mL | 0.8296 mL | 1.6592 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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