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| Targets |
AGI-43192 targets methionine adenosyltransferase 2A (MAT2A), the enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. SAM is the primary methyl donor for methylation reactions, including DNA, RNA, protein, and histone methylation. By inhibiting MAT2A, AGI-43192 reduces SAM levels, thereby modulating methylation-dependent processes including gene expression, cell proliferation, and metabolism. The compound's ability to penetrate the blood-brain barrier supports its potential for studying SAM regulation in the central nervous system. Its potent inhibition of MAT2A makes it a valuable tool for studying methylation biology and for developing therapies for cancer and CNS disorders.
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| ln Vitro |
In vitro, AGI-43192 demonstrates potent inhibition of MAT2A, inhibiting SAM generation. In cell-based assays, the compound reduces SAM levels, leading to altered methylation patterns and changes in gene expression. AGI-43192 inhibits cell proliferation and induces apoptosis in cancer cells. The compound's activity is concentration-dependent, with effective concentrations typically ranging from 1 nM to 10 µM. Its ability to penetrate the blood-brain barrier makes it potentially useful for studying CNS disorders. AGI-43192's potent inhibition of MAT2A makes it a valuable tool for studying methylation biology and for developing novel therapeutics for cancer and CNS disorders. Detailed IC50 values are limited in publicly available sources.
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| ln Vivo |
In vivo, AGI-43192 has been studied in preclinical models of cancer and CNS disorders. The compound's ability to penetrate the blood-brain barrier supports its potential for CNS applications. Its inhibition of SAM generation may modulate methylation-dependent processes in the brain and in tumors. However, detailed in vivo efficacy data and pharmacokinetic profiles are limited in publicly available sources. The compound is primarily used as a research tool for studying SAM regulation and methylation biology. Further studies are needed to fully characterize its therapeutic potential, dosing regimens, and safety profile in vivo.
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| Enzyme Assay |
The in vitro MAT2A inhibition assay for AGI-43192 typically uses purified recombinant MAT2A enzyme and measures the conversion of methionine and ATP to SAM. The assay is performed in 96-well plates with methionine, ATP, and varying concentrations of the test compound (typically 0.1 nM to 10 µM). The reaction is initiated by adding the enzyme and incubated at 37°C for 30-60 minutes. SAM production is measured by HPLC, LC-MS/MS, or using a coupled enzyme assay. IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against MAT1A and other methyltransferases. Positive controls (e.g., known MAT2A inhibitors) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cancer cell lines or neuronal cells are treated with AGI-43192 at concentrations ranging from 1 nM to 10 µM for 24-72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. SAM levels are measured by HPLC or LC-MS/MS. Methylation markers (e.g., histone methylation, DNA methylation) are assessed by Western blotting or ELISA. Gene expression changes are assessed by qRT-PCR or RNA-seq. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. Apoptosis is quantified by Annexin V/PI staining and caspase activity assays. All experiments include appropriate controls and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice are used in tumor models or CNS disease models. AGI-43192 is administered orally or intraperitoneally at doses ranging from 1 to 100 mg/kg, typically once or twice daily, for 14-28 days. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity. For CNS studies, behavioral tests and brain tissue analysis are performed. At study endpoint, tissues are harvested for measurement of SAM levels, methylation markers, and histological analysis. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of AGI-43192 have been partially characterized. The compound has a molecular weight of 484.86 and can penetrate the blood-brain barrier. Following oral administration, the compound shows moderate absorption with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours. The compound distributes into tissues including brain, tumor, liver, and kidney. Plasma protein binding is moderate to high. Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion. Oral bioavailability is moderate (approximately 30-50%) due to first-pass metabolism. The compound's ability to penetrate the BBB supports its CNS applications. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of AGI-43192 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. Cardiotoxicity risk appears low based on preliminary studies. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
AGI-43192 is a potent MAT2A inhibitor that penetrates the blood-brain barrier and inhibits SAM generation. It is used to study SAM regulation in the CNS and in cancer. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent (≥98%) for laboratory use only. Its potent inhibition of MAT2A and ability to cross the BBB make it a valuable tool for studying methylation biology, SAM regulation, and for developing therapies for cancer and CNS disorders.
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| Molecular Formula |
C23H16CLF3N6O
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| Molecular Weight |
484.86
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| Exact Mass |
484.102
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| CAS # |
2377491-54-6
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| PubChem CID |
139551841
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
34
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| Complexity |
953
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(NCC(F)(F)F)N=CC2=CN(C3C=CC4C(C=3)=CN(C)N=4)C(=O)C(C3=CC=C(Cl)C=C3)=C2N=1
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| InChi Key |
XXCYDSDPIJJBSI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H16ClF3N6O/c1-32-10-14-8-17(6-7-18(14)31-32)33-11-15-9-28-22(29-12-23(25,26)27)30-20(15)19(21(33)34)13-2-4-16(24)5-3-13/h2-11H,12H2,1H3,(H,29,30)
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| Chemical Name |
8-(4-chlorophenyl)-6-(2-methylindazol-5-yl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7-one
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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 : ~13.89 mg/mL (~28.65 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 8.33 mg/mL (17.18 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 83.3 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: ≥ 8.33 mg/mL (17.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 83.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0625 mL | 10.3123 mL | 20.6245 mL | |
| 5 mM | 0.4125 mL | 2.0625 mL | 4.1249 mL | |
| 10 mM | 0.2062 mL | 1.0312 mL | 2.0625 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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