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| Targets |
Kinetoplastid proteasome (20S proteasome). GNF6702 is a selective, non-competitive, allosteric inhibitor of the kinetoplastid proteasome that specifically targets the chymotrypsin-like (CT-L) activity of the T. cruzi proteasome. It acts as an allosteric proteasome inhibitor that does not compete with the substrate for the active site. The compound displays no inhibitory effect on the caspase-like (C-L) and trypsin-like (T-L) activities of the parasite proteasome (IC50 >10 μM), and importantly, does not inhibit the mammalian proteasome or the growth of mammalian cells. This selectivity profile is critical for its therapeutic potential as it minimizes toxicity to host cells while effectively targeting the parasite.
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| ln Vitro |
GNF6702 inhibits the chymotrypsin-like activity of the T. cruzi proteasome with an IC50 of 35 nM. In contrast, bortezomib inhibits the chymotrypsin-like activity with an IC50 of 91 nM. GNF6702 displays no inhibitory effect on caspase-like and trypsin-like activities of the parasite proteasome (IC50 >10 μM). The compound does not inhibit the mammalian proteasome or growth of mammalian cells, demonstrating excellent selectivity for the parasite target. This selectivity is achieved through binding to a unique allosteric site on the kinetoplastid proteasome that is not conserved in the mammalian proteasome.
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| ln Vivo |
GNF6702 clears parasites in mouse models of kinetoplastid infections, including leishmaniasis, Chagas disease, and human African trypanosomiasis. In T. brucei-infected mice, treatment with GNF6702 by oral administration once-daily for 7 days effectively clears the parasites. The compound shows favorable in vivo pharmacokinetics and significant brain penetration, which enables oral dosing and achieves complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection models of human African trypanosomiasis. GNF6702 is well-tolerated in mice, with little evident toxicity to mammalian cells, supporting its potential as a safe and effective treatment for these neglected tropical diseases.
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| Enzyme Assay |
Kinetoplastid proteasome inhibition is assessed using in vitro enzyme assays with purified T. cruzi or T. brucei 20S proteasome and fluorogenic peptide substrates. Chymotrypsin-like activity is measured using the substrate Suc-LLVY-AMC, caspase-like activity using Z-LLE-AMC, and trypsin-like activity using Boc-LRR-AMC. The release of the fluorescent AMC (7-amino-4-methylcoumarin) group is monitored continuously or at endpoint using a fluorescence plate reader (excitation ~380 nm, emission ~460 nm). IC50 values are calculated from dose-response curves using nonlinear regression analysis. Selectivity is evaluated by testing the compound against mammalian 20S proteasome and by profiling against a panel of related proteases and kinases.
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| Cell Assay |
Cellular activity is evaluated in parasite cultures of T. cruzi, Leishmania spp., and T. brucei. Parasites are grown in appropriate culture media and treated with GNF6702 at various concentrations (typically 0.001-100 μM) for 24-72 hours. Parasite viability is assessed using resazurin-based assays (Alamar Blue), ATP-lite luminescence assays, or by direct counting of motile parasites. Selectivity for parasite over mammalian cells is confirmed by parallel testing in mammalian cell lines such as HepG2, HEK293, or J774 macrophages, where cell viability is assessed by MTT or similar assays. The reduction of intracellular 2-HG levels may be measured by LC-MS in relevant cell models.
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| Animal Protocol |
In vivo efficacy is studied in mouse models of leishmaniasis, Chagas disease, and human African trypanosomiasis. For T. brucei infection models, mice are infected with T. brucei parasites and treated with GNF6702 by oral administration once-daily for 7 days. Parasite load is measured in blood by microscopy or quantitative PCR, and in tissues (spleen, liver, brain) by organ burden analysis. Survival is monitored over the course of the study. In visceral leishmaniasis models, parasite burden in the liver and spleen is assessed. In Chagas disease models, parasitemia and tissue parasite load are measured. Pharmacokinetic/pharmacodynamic (PK/PD) relationships are established by measuring free plasma concentrations of GNF6702 and correlating with parasite clearance. The compound's brain penetration is assessed by measuring total GNF6702 concentration in mouse plasma and brain after single oral dose (20 mg/kg).
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| ADME/Pharmacokinetics |
GNF6702 has a molecular formula of C22H16FN7O2 and a molecular weight of 429.4 g/mol. The compound shows favorable in vivo pharmacokinetics with significant brain penetration. In mouse models of visceral leishmaniasis, free plasma concentration profiles have been characterized, with free GNF6702 concentration values predicted from measured total plasma concentration values collected on day 1 and day 8 of treatment. The compound exhibits good oral bioavailability and is well-tolerated in mice. Detailed pharmacokinetic parameters including half-life, volume of distribution, and clearance are available from the primary literature. The compound is soluble in DMSO and should be stored at -20°C for long-term stability.
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| Toxicity/Toxicokinetics |
Safety data indicate GNF6702 does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. The compound has little evident toxicity to mammalian cells at concentrations that effectively kill parasites. In toxicology studies, mice were treated with GNF6702 at doses of 3-300 mg/kg/day for 13 weeks, rats at 3-300 mg/kg/day for 26 weeks, and rabbits at 5-30 mg/kg/day for 2 weeks. As a research compound, GNF6702 should be handled with standard laboratory safety precautions. The compound is for research use only and not for human therapeutic applications without appropriate regulatory approval.
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| References | |
| Additional Infomation |
GNF6702 is an aromatic amide formed by the condensation of the carboxyl group of 2,4-dimethyl-1,3-oxazol-5-carboxylic acid with the aromatic amino group of 4-fluoro-3-[6-(pyridin-2-yl)[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]aniline. It is a proteasome inhibitor known to be effective against three parasites that cause Chagas disease, leishmaniasis, and sleeping sickness. It is both a proteasome inhibitor and an anti-leishmaniasis drug. GNF6702 belongs to the triazolopyrimidine, pyridine, monofluorobenzene, 1,3-oxazolidine, cyclic, and aromatic amide classes.
GNF6702 is a research tool compound for studying kinetoplastid proteasome biology and developing treatments for neglected tropical diseases. It is not approved for clinical use and is intended for research purposes only. The compound has been investigated for Chagas disease, leishmaniasis, and human African trypanosomiasis. A key reference is Khare S, et al. Nature. 2016 Sep 8;537(7619):229-233, which describes the discovery and characterization of GNF6702 as a selective inhibitor of the kinetoplastid proteasome. The compound's ability to achieve complete cure in both hemolymphatic and meningoencephalic infection models of human African trypanosomiasis makes it a promising lead for further development. GNF6702 represents a significant advance in the search for new treatments for neglected tropical diseases that affect millions of people worldwide. |
| Molecular Formula |
C22H16FN7O2
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|---|---|
| Molecular Weight |
429.4154
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| Exact Mass |
429.134
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| CAS # |
1799329-72-8
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| PubChem CID |
91810392
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.733
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| LogP |
0.88
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
672
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC=C(C=C1C1N=C2N=CC(C3C=CC=CN=3)=CN2N=1)NC(C1=C(C)N=C(C)O1)=O
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| InChi Key |
WXZFCGRYVWYYTG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H16FN7O2/c1-12-19(32-13(2)26-12)21(31)27-15-6-7-17(23)16(9-15)20-28-22-25-10-14(11-30(22)29-20)18-5-3-4-8-24-18/h3-11H,1-2H3,(H,27,31)
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| Chemical Name |
N-[4-fluoro-3-(6-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide
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| Synonyms |
GNF 6702; GNF-6702; GNF6702
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3287 mL | 11.6436 mL | 23.2872 mL | |
| 5 mM | 0.4657 mL | 2.3287 mL | 4.6574 mL | |
| 10 mM | 0.2329 mL | 1.1644 mL | 2.3287 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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