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GCN2iB is a novel, potent and ATP-competitive inhibitor, has an IC50 of 2.4 nM for the serine/threonine protein kinase general control nonderepressible 2 (GCN2). Cancer therapy may benefit from the application of GCN2iB. Cancer cells that express asparagine synthetase (ASNS) at low basal levels are more susceptible to the antileukemic agent L-asparaginase (ASNase) both in vitro and in vivo when GCN2 is inhibited.
| Targets |
GCN2 (IC50 = 2.4 nM)
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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].
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| 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].
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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].
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| References |
| Molecular Formula |
C18H12CLF2N5O3S
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|---|---|
| Molecular Weight |
451.8344
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| Exact Mass |
451.0317445
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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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| Appearance |
Solid
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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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| 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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