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Purity: ≥98%
AGI-6780 (AGI6780; AGI 6780) is a potent and selective inhibitor of tumor-associated mutant IDH2 (isocitrate dehydrogenases 2) R140Q with potential anti-inflammatory activity. It inhibits IDH2 R140Q with an IC50 of 23 nM. It shows less potency against IDH2(WT) with an IC50 of 190±8.1 nM.
| Targets |
Mutant isocitrate dehydrogenase 2 (IDH2) (Ki = 0.07 μM for IDH2 R140Q; Ki = 0.16 μM for IDH2 R172K; negligible affinity for wild-type IDH2) [1]
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| ln Vitro |
Human glioblastoma U87 and TF-1 cells expressing IDH2R140Q are tested for AGI-6780, with IC50 values of 11±2.6 nM, 18±0.51 nM, and >1 mM, respectively, after 48 hours of incubation. When AGI-6780 is administered to TF-1R140Q cells at concentrations that bring down 2HG to nearly normal physiological levels, both the expression of the HBG and KLF1 genes as well as the differentiation-associated color change are restored. In TF-1 cells, AGI-6780 can undo the differentiation block caused by IDH2R140Q. Before undergoing EPO-induced differentiation, the TF1R140Q cells' intracellular concentration of (R)-2-hydroxyglutarate was significantly reduced by pretreatment with AGI-6780 (0.2 μM and 1 μM)[1].
In leukemia cell lines expressing IDH2 R140Q (TF-1) or IDH2 R172K (Kasumi-1), AGI-6780 inhibited the production of the oncogenic metabolite 2-hydroxyglutarate (2-HG) with an IC50 of ~0.3 μM [1] Treatment with AGI-6780 induced myeloid differentiation, as evidenced by increased expression of the differentiation marker CD11b and decreased expression of the stem cell marker CD34 (flow cytometry analysis) [1] The drug suppressed leukemia cell proliferation (CCK-8 and BrdU incorporation assays) and promoted apoptosis (Annexin V/PI staining), with a 50% reduction in cell viability at 1 μM after 72 hours of incubation [1] Western blot analysis showed downregulation of HIF-1α and upregulation of differentiation-related proteins (e.g., CEBPA), while PCR results indicated increased mRNA levels of myeloid differentiation genes (e.g., PU.1) [1] No significant inhibition of wild-type IDH2 or IDH1 activity was observed at concentrations up to 10 μM, demonstrating high target selectivity [1] |
| ln Vivo |
In a xenograft mouse model engrafted with IDH2 R140Q-expressing leukemia cells, intraperitoneal administration of AGI-6780 (50 mg/kg, twice daily for 21 days) significantly reduced 2-HG levels in bone marrow and spleen (by ~70% compared to vehicle control) [1]
The drug decreased leukemia cell burden in peripheral blood, bone marrow, and spleen (flow cytometry and histopathological analysis), with a ~60% reduction in bone marrow blasts [1] AGI-6780 prolonged the overall survival of xenograft mice, with a median survival extension of 12 days compared to the vehicle group [1] Histological examination of major organs (liver, kidney, heart, lung) revealed no obvious toxic lesions, and myeloid differentiation of leukemia cells was confirmed in mouse bone marrow [1] |
| Enzyme Assay |
Recombinant wild-type or mutant IDH2 (R140Q/R172K) was incubated with substrates (isocitrate and NADPH) and serial concentrations of AGI-6780 at 37°C for 30 minutes [1]
IDH2 enzyme activity was measured by monitoring the consumption of NADPH via spectrophotometry at 340 nm, with enzyme inhibition rate calculated based on absorbance changes [1] Ki values were determined by fitting the inhibition data to a competitive binding model, with negative controls (vehicle-only reactions) and positive controls (non-selective IDH inhibitors) included to validate assay specificity [1] |
| Cell Assay |
Leukemia cell lines (TF-1 IDH2 R140Q, Kasumi-1 IDH2 R172K) were cultured in serum-supplemented medium and seeded into 96-well plates at a density of 5×10^4 cells/well [1]
Cells were treated with AGI-6780 at concentrations ranging from 0.01 to 10 μM, with vehicle (DMSO) as control, and incubated at 37°C in a 5% CO2 incubator for 24–72 hours [1] 2-HG levels in cell lysates were quantified by liquid chromatography-mass spectrometry (LC-MS) after protein precipitation [1] Differentiation markers (CD11b, CD34) were analyzed by flow cytometry; proliferation was assessed via CCK-8 assay (absorbance at 450 nm) or Brdu incorporation (immunofluorescence staining); apoptosis was detected by Annexin V/PI double staining and flow cytometry [1] Western blot was performed to detect protein expression (HIF-1α, CEBPA) using specific primary antibodies and horseradish peroxidase-conjugated secondary antibodies; mRNA levels of differentiation genes were measured by quantitative real-time PCR [1] |
| Animal Protocol |
Immunodeficient NSG mice (6–8 weeks old) were intravenously injected with 1×10^6 IDH2 R140Q-expressing leukemia cells to establish the xenograft model [1]
Seven days after cell inoculation, mice were randomly divided into treatment and control groups (n=8 per group); the treatment group received intraperitoneal injections of AGI-6780 dissolved in 5% DMSO + 30% PEG400 + 65% normal saline at 50 mg/kg, twice daily for 21 days [1] The control group received equal volumes of the vehicle solution on the same schedule [1] During the experiment, mice were monitored for body weight, activity, and survival status; peripheral blood samples were collected weekly to analyze leukemia cell proportions via flow cytometry [1] At the end of treatment or when mice reached humane endpoints, bone marrow, spleen, liver, and kidney tissues were harvested for 2-HG quantification (LC-MS), flow cytometric analysis of leukemia cell burden, and histopathological examination (H&E staining) [1] |
| Toxicity/Toxicokinetics |
In xenograft mice treated with AGI-6780 (50 mg/kg, twice daily for 21 days), no significant change in body weight was observed compared to the vector group [1]. Serum biochemical analysis showed normal levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen, indicating no significant hepatotoxicity or nephrotoxicity [1]. Histopathological examination of major organs (liver, kidney, heart, lung, spleen) revealed no abnormal lesions or inflammatory reactions [1].
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| References | |
| Additional Infomation |
AGI-6780 is a first-in-class selective small-molecule IDH2 mutation inhibitor that does not cross-react with wild-type IDH2 or IDH1 [1]. Its anti-leukemic mechanism involves binding to the active site of mutant IDH2, inhibiting its enzyme activity, thereby reducing the production of 2-HG, reversing the differentiation arrest of leukemia cells, and restoring normal myeloid differentiation [1]. This drug was initially developed for the treatment of acute myeloid leukemia (AML) carrying IDH2 mutations, a subtype of AML with poor prognosis and limited treatment options [1]. As of the time of publication (2013), AGI-6780 is in the preclinical development stage, laying the foundation for subsequent clinical trials of mutant IDH2 inhibitors [1].
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| Molecular Formula |
C21H18F3N3O3S2
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| Molecular Weight |
481.51
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| Exact Mass |
481.074
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| CAS # |
1432660-47-3
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| Related CAS # |
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| PubChem CID |
71299339
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.652
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| LogP |
4.42
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
771
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
CCAWRGNYALGPQH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H18F3N3O3S2/c22-21(23,24)14-2-1-3-16(10-14)25-20(28)26-19-11-17(32(29,30)27-15-4-5-15)6-7-18(19)13-8-9-31-12-13/h1-3,6-12,15,27H,4-5H2,(H2,25,26,28)
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| Chemical Name |
1-[5-(cyclopropylsulfamoyl)-2-thiophen-3-ylphenyl]-3-[3-(trifluoromethyl)phenyl]urea
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.19 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 25.0 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: ≥ 2.5 mg/mL (5.19 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 25.0 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 | 2.0768 mL | 10.3840 mL | 20.7680 mL | |
| 5 mM | 0.4154 mL | 2.0768 mL | 4.1536 mL | |
| 10 mM | 0.2077 mL | 1.0384 mL | 2.0768 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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