| Size | Price | Stock | Qty |
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| Targets |
GCN2
GCN2-IN-6 targets GCN2, a serine/threonine kinase that is activated in response to amino acid deprivation, UV irradiation, and other stress conditions. GCN2 phosphorylates eIF2α, leading to attenuation of global protein synthesis and activation of stress-responsive gene expression. GCN2-IN-6 inhibits GCN2 kinase activity with high potency (IC50 = 1.8 nM in enzymatic assays). The compound also inhibits PERK (IC50 = 0.26 nM), another eIF2α kinase that is activated by endoplasmic reticulum stress. By inhibiting these kinases, GCN2-IN-6 modulates the integrated stress response pathway, which is involved in cellular adaptation to various stressors. The compound's ability to modulate stress-related translational control makes it an essential research tool for exploring therapeutic strategies targeting nutrient sensing and stress response mechanisms. |
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| ln Vitro |
In acute lymphoblastic leukemia (ALL) CCRFCEM cells, GCN2-IN-6 (compound 6d) was applied in the presence of asparaginase, an asparagine-depleting agent, to investigate the impact of GCN2 inhibition on cancer cell proliferation. The CCRF-CEM cells' sensitivity to asparaginase was significantly enhanced by treatment with GCN2-IN-6. GCN2 wild-type (WT) mouse embryonic fibroblasts (MEFs) showed a slight antiproliferative impact from combined asparaginase and GCN2-IN-6 treatment, while GCN2 knockout (KO) MEFs did not show this effect. ATF4, p-eIF2α, and GCN2-IN-6 are all inhibited by asparaginase[1].
In vitro, GCN2-IN-6 has been characterized as a potent inhibitor of GCN2 and PERK kinases. Enzymatic assays have confirmed an IC50 of 1.8 nM for GCN2 inhibition and 0.26 nM for PERK inhibition. Cellular assays demonstrate IC50 values of 9.3 nM for GCN2 and 230 nM for PERK, indicating that the compound is cell-permeable and retains its inhibitory activity in a cellular context. The compound's ability to inhibit both GCN2 and PERK makes it useful for studying the integrated stress response pathway and its role in various diseases. Its potent activity and oral availability support its use in both in vitro and in vivo studies. |
| ln Vivo |
GCN2-IN-6 (Compound 6d; 0.3-3 mg/kg; oral) at 3 mg/kg suppresses the autophosphorylation of GCN2 and the downstream effector ATF4 to basal levels following asparaginase pretreatment [1].
In vivo, GCN2-IN-6 has been studied in animal models of diseases where ISR signaling is dysregulated. As an orally available compound, it can be administered to mice and other animals to evaluate its effects on stress response pathways. The compound is valuable for studying cancer, neurodegeneration, and metabolic disorders. Its ability to modulate stress-related translational control makes it useful for exploring therapeutic strategies targeting nutrient sensing and stress response mechanisms. Detailed in vivo efficacy studies are described in the primary literature. The compound's oral bioavailability and pharmacokinetic profile support its use in animal models for proof-of-concept studies. |
| Enzyme Assay |
For in vitro enzyme assays, GCN2-IN-6 is evaluated for its ability to inhibit GCN2 and PERK kinase activity. Kinase assays are performed using recombinant GCN2 or PERK proteins and appropriate peptide substrates, measuring phosphorylation using radiolabeled ATP or fluorescence-based detection methods. IC50 values are determined from dose-response curves. Selectivity profiling against a panel of kinases is performed to assess specificity. Enzyme kinetics studies determine the mode of inhibition (competitive, non-competitive, or uncompetitive) and provide mechanistic insights. These cell-free assays help characterize the compound's potency and selectivity as a kinase inhibitor.
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| Cell Assay |
In vitro cellular assays for GCN2-IN-6 are performed using cell lines that express GCN2 and PERK. Cells are treated with the compound at various concentrations, and eIF2α phosphorylation is measured by Western blotting using phospho-specific antibodies. Cellular IC50 values are determined from dose-response curves. The compound's effects on downstream targets such as ATF4 and CHOP expression are assessed by Western blotting or qPCR. Cell viability and proliferation assays are performed to evaluate functional consequences of GCN2/PERK inhibition. The compound's ability to modulate the integrated stress response is confirmed by assessing translation rates using puromycin incorporation or polysome profiling. Selectivity is confirmed by comparing effects in wild-type versus GCN2 or PERK knockout cells.
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| Animal Protocol |
Animal/Disease Models: Mice bearing CCRF-CEM cells xenografts[1]
Doses: 0.3 mg/kg, 1 mg/kg, and 3 mg/kg Route of Administration: Oral administration; for 8 hrs (hours) Experimental Results: Suppressed both self-phosphorylation of GCN2 and the downstream effector ATF4 to the basal level following pretreatment with asparaginase. In vivo animal experiments with GCN2-IN-6 are conducted in disease models where ISR signaling is implicated. Cancer models include tumor xenografts where GCN2 inhibition may sensitize tumors to nutrient deprivation or chemotherapy. Neurodegeneration models include conditions where ER stress and PERK activation contribute to pathology. Metabolic disorder models include conditions where nutrient sensing and stress response are dysregulated. GCN2-IN-6 is administered orally at doses determined from pharmacokinetic studies. Efficacy endpoints include tumor growth inhibition, improvement in neurological function, or normalization of metabolic parameters. Pharmacodynamic markers such as eIF2α phosphorylation and ATF4 expression are measured in tissues. The compound's oral availability supports convenient dosing regimens. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of GCN2-IN-6 have been characterized to support its use in in vivo studies. The compound is orally available, indicating good absorption following oral administration. Detailed PK parameters such as half-life, Cmax, Tmax, AUC, volume of distribution, and clearance have been determined in preclinical studies. The compound's favorable pharmacokinetic profile supports its use in animal models for proof-of-concept studies. Protein binding and tissue distribution have also been characterized. Metabolic stability has been assessed to identify potential metabolic pathways and drug-drug interactions. Formulation development has been optimized for oral administration. The compound's PK properties are described in the primary literature.
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| Toxicity/Toxicokinetics |
The toxicological profile of GCN2-IN-6 has been evaluated in preclinical studies. As a kinase inhibitor that modulates the integrated stress response, its safety profile is important for its use as a research tool and potential therapeutic agent. In vitro cytotoxicity assays using multiple cell lines provide initial safety information. In vivo tolerability studies in rodents assess maximum tolerated dose and identify potential target organs of toxicity. Parameters assessed include body weight, clinical signs, hematology, clinical chemistry, and histopathology. The compound is intended for research use only and not for human therapeutic applications without appropriate regulatory approval. Researchers should follow standard laboratory safety practices when handling GCN2-IN-6.
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| References | |
| Additional Infomation |
GCN2-IN-6 is a valuable research tool for studying the integrated stress response (ISR) pathway and its role in various diseases. The compound is used to investigate the mechanisms of GCN2 and PERK signaling and their contributions to cancer progression, neurodegeneration, and metabolic disorders. Its ability to modulate stress-related translational control makes it useful for exploring therapeutic strategies targeting nutrient sensing and stress response mechanisms. GCN2-IN-6 can be employed to validate GCN2 and PERK as therapeutic targets and to study the functional consequences of ISR modulation in disease models. The compound's potency and oral availability support its use in both in vitro mechanistic studies and in vivo efficacy studies.
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| Molecular Formula |
C19H12CL2F2N4O3S
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|---|---|
| Molecular Weight |
485.291387557983
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| Exact Mass |
483.997
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| CAS # |
2183470-09-7
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| PubChem CID |
137347437
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
782
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(CO)=CC(=CC=1S(NC1C=CC(=C(C#CC2=CN=C(N)N=C2)C=1F)F)(=O)=O)Cl
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| InChi Key |
VJXAWOQPYMAEFQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H12Cl2F2N4O3S/c20-12-5-11(9-28)17(21)16(6-12)31(29,30)27-15-4-3-14(22)13(18(15)23)2-1-10-7-25-19(24)26-8-10/h3-8,27-28H,9H2,(H2,24,25,26)
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| Chemical Name |
N-[3-[2-(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl]-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide
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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 : 250 mg/mL (515.16 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.29 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 20.8 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: ≥ 2.08 mg/mL (4.29 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 20.8 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 | 2.0606 mL | 10.3031 mL | 20.6062 mL | |
| 5 mM | 0.4121 mL | 2.0606 mL | 4.1212 mL | |
| 10 mM | 0.2061 mL | 1.0303 mL | 2.0606 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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