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| Targets |
GCN2 (IC50 = 2.4 nM)
GCN2iB targets general control nonderepressible 2 kinase (GCN2), a serine/threonine-protein kinase that is involved in the regulation of cellular stress responses. GCN2 is activated by amino acid starvation and other stress signals, leading to phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and subsequent inhibition of protein synthesis. GCN2iB acts as an ATP-competitive inhibitor with an IC₅0 of 2.4 nM. By inhibiting GCN2, the compound modulates the integrated stress response. |
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| ln Vitro |
GCN2iB demonstrates strong cellular activity and an IC50 value of 2.4 nM for GCN2. Only GCN2 exhibits >99.5% inhibition in a panel of 468 kinases, and three kinases (MAP2K5, STK10, and ZAK) exhibit high kinase selectivity at 1 μM GCN2iB, with >95% inhibition[1].
In vitro, GCN2iB is a potent and selective inhibitor of GCN2 with an IC₅0 of 2.4 nM. It is an ATP-competitive inhibitor. GCN2iB is selective for GCN2 over a panel of 465 kinases, although it does inhibit MAP2K5, EIF2AK2, and MAP3K20 at 1 uM. The compound has potential therapeutic applications in various diseases, including cancer, neurodegenerative disorders, and viral infections. Its potent inhibitory activity makes it a valuable tool for studying GCN2 biology. |
| ln Vivo |
GCN2iB or ASNase by themselves do not substantially slow tumor growth in the CCRF-CEM xenograft antitumor activity study. Most remarkably, synergistic effects of ASNase and GCN2iB result in strong antitumor activity (P=0.0002). A synergistic effect of GCN2iB and ASNase is observed in MV-4-11 and SU.86.86 xenografts, respectively, demonstrating strong antitumor activity. Even after the drugs stop working, tumors treated with ASNase/GCN2iB do not grow significantly. ASNase and GCN2iB work in concert to produce a synergistic effect that increases survival when compared to the vehicle-treated control[1].
In vivo studies of GCN2iB are focused on evaluating its efficacy in animal models of diseases where GCN2 plays a role, such as cancer, neurodegenerative disorders, and viral infections. As a potent and selective GCN2 inhibitor with an IC₅0 of 2.4 nM, the compound is expected to demonstrate significant effects on the integrated stress response in vivo. Further in vivo studies are needed to fully characterize its pharmacokinetic properties, bioavailability, and efficacy in various disease models. |
| Enzyme Assay |
For in vitro enzyme/receptor binding assays, GCN2iB is evaluated using kinase activity assays that measure GCN2-mediated phosphorylation of eIF2alpha or peptide substrates. The compound is incubated with recombinant GCN2 kinase and ATP at various concentrations. Kinase activity is quantified by measuring phosphorylation using radiometric, fluorescence-based, or ELISA methods. IC₅0 values are determined from dose-response curves. The ATP-competitive nature of inhibition can be confirmed by kinetic analysis. Selectivity profiling against other kinases is performed to confirm specificity.
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| Cell Assay |
For in vitro cellular experiments, GCN2iB is tested in cell lines to evaluate its effects on GCN2 activity and the integrated stress response. Cells are cultured in appropriate media and treated with various concentrations of the compound. GCN2 activity is assessed by measuring eIF2alpha phosphorylation using Western blotting. The compound's effects on protein synthesis, cell viability, and stress response pathways are evaluated. Its effects on GCN2-dependent signaling are further investigated using appropriate cellular models of stress.
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| Animal Protocol |
Mice: In 6-week-old female SCID mice, a suspension of CCRF-CEM, HPB-ALL, MV-4-11, or SU.86.86 cells (1×107 cells/site) is subcutaneously injected into the right flanks. Tumor volume is computed as volume = L×l2×1/2, where l is the corresponding perpendicular distance and L is the longest diameter across the tumor. Weight of the body is also measured. Mice with tumor masses less than 200 mm3 are divided into treatment groups (N=5) in order to measure the anti-tumor activity. When an endpoint is reached or the study's conclusion occurs, the tumors are tracked and the mice are put to death. Starting on the day following randomization, mice containing the xenografts are given either intraperitoneally or orally GCN2 inhibitors (e.g., GCN2iB, 10 mpk, twice daily) or ASNase for a duration of 7 to 10 days, respectively. The mean change in tumor volume over the course of treatment in the control and treated groups is compared to determine T/C (%), an index of anti-tumor activity[1].
For in vivo animal experiments, GCN2iB 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 models of cancer, neurodegenerative disorders, or viral infections. Typical dosing regimens may range from 1 to 50 mg/kg. Pharmacodynamic markers such as eIF2alpha phosphorylation are measured in tissues. Disease progression and physiological parameters are assessed. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of GCN2iB are not extensively detailed in the public literature. As a small molecule with a molecular weight of 451.83, it may have reasonable oral bioavailability and tissue distribution. The compound is soluble in DMSO. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies. The compound's metabolism and excretion pathways remain to be fully characterized.
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| Toxicity/Toxicokinetics |
Toxicological data for GCN2iB are limited, as it is primarily a research tool. As a GCN2 inhibitor, its toxicity would depend on the importance of GCN2 for normal cellular stress responses. GCN2 is involved in the integrated stress response, and its inhibition could affect cellular adaptation to stress. Comprehensive toxicology studies including acute and repeated-dose toxicity, genotoxicity, and cardiotoxicity assessments would be needed for further development. Appropriate safety precautions should be taken when handling this compound.
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| References | |
| Additional Infomation |
ATP-competitive inhibitors of Gcn2 protein kinase
GCN2iB is a research compound used to study GCN2 biology and develop therapies for GCN2-related diseases. 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 potent and ATP-competitive GCN2 inhibitor with an IC₅0 of 2.4 nM and has potential applications in cancer, neurodegenerative disorders, and viral infections. |
| Molecular Formula |
C18H12CLF2N5O3S
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|---|---|
| Molecular Weight |
451.8344
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| Exact Mass |
451.031
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| CAS # |
2183470-12-2
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| Related CAS # |
2183470-12-2; 2183470-13-3 (acetate)
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| PubChem CID |
134814489
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| Appearance |
Off-white to light yellow solid
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
750
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=C(C=C(C=N1)Cl)S(=O)(=O)NC2=C(C(=C(C=C2)F)C#CC3=CN=C(N=C3)N)F
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| InChi Key |
JGHVXJKGYJYWOP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H12ClF2N5O3S/c1-29-17-15(6-11(19)9-23-17)30(27,28)26-14-5-4-13(20)12(16(14)21)3-2-10-7-24-18(22)25-8-10/h4-9,26H,1H3,(H2,22,24,25)
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| Chemical Name |
N-[3-[2-(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide
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| Synonyms |
GCN2iB
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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: 15~50 mg/mL (33.2~110.7 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.70 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. Solubility in Formulation 2: ≥ 1.67 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2132 mL | 11.0661 mL | 22.1322 mL | |
| 5 mM | 0.4426 mL | 2.2132 mL | 4.4264 mL | |
| 10 mM | 0.2213 mL | 1.1066 mL | 2.2132 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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