| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
GSK3β 16 nM (IC50) DYRK1A 6 nM (IC50)
GNF4877 targets DYRK1A and GSK3β. It is a potent dual inhibitor with IC50s of 6 nM for DYRK1A and 16 nM for GSK3β. By inhibiting these kinases, it blocks NFATc nuclear export and promotes β-cell proliferation. DYRK1A and GSK3β are kinases involved in the regulation of β-cell proliferation and function. |
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| ln Vitro |
Increased intracellular Ca2+ leads to the activation of calcineurin and the nuclear translocation of NFATc proteins, while high glucose concentrations and glucokinase activators (GKAs) boost Ca2+ signaling in β-cells. In fact, when high glucose or pharmacological glucokinase activators are present, GNF4877 doses (0.1 μM, 0.3 μM) much below the EC50 for β-cell proliferation can stimulate proliferation. Finally, glibenclamide, a sulfonylurea receptor 1 inhibitor, or Bay K8644, an L-type Ca2+ channel activator, both increase intracellular Ca2+ and have additive action when combined with GNF4877[1].
GNF4877 demonstrates potent in vitro activity as a DYRK1A and GSK3β inhibitor with IC50s of 6 nM and 16 nM, respectively. It leads to the blockade of NFATc nuclear export and increased β-cell proliferation, with an EC50 of 0.66 μM for mouse β (R7T1) cells. In cell-based assays, GNF4877 promotes β-cell proliferation and enhances insulin secretion. |
| ln Vivo |
GNF4877 therapy (50 mg/kg; twice daily; oral gavage; for 15 days; double transgenic RIP-DTA male mice) improves glycaemic control, enhances β-cell mass and insulin content, and promotes β-cell proliferation[1].
GNF4877 has been shown to reduce blood glucose levels in an oral glucose tolerance test (OGTT) in a transgenic RIP-DTA mouse model of type I diabetes when administered at a dose of 50 mg/kg twice per day. This demonstrates its potential as a therapeutic agent for diabetes. The compound's ability to promote β-cell proliferation and improve glucose tolerance is a key measure of its in vivo efficacy. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (non-cell-based) assay for GNF4877 involves assessing its inhibition of DYRK1A and GSK3β kinase activities. Recombinant DYRK1A and GSK3β are incubated with the compound, ATP, and substrate peptides. Kinase activity is measured by detecting the phosphorylation of the substrates. The IC50 values of 6 nM and 16 nM are determined from dose-response curves.
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| Cell Assay |
The in vitro cell-based assay for GNF4877 involves treating pancreatic β-cells with the compound and measuring its effects on cell proliferation. The compound's ability to increase β-cell proliferation is assessed, with an EC50 of 0.66 μM for mouse β (R7T1) cells. The blockade of NFATc nuclear export is also measured.
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| Animal Protocol |
Animal/Disease Models: Double transgenic RIP-DTA male mice (Tg (Ins 2-rtTA) 2 Efr Tg (teto-DTA) 1 Gfi/J) with Doxycycline (28.8±2.4 g; 82±2 days)[1]
Doses: 50 mg/kg Route of Administration: Oral gavage; twice a day; for 15 days Experimental Results: Induced β-cell proliferation, increased β-cell mass and insulin content, and improved glycaemic control. In vivo animal experiments for GNF4877 are conducted in the RIP-DTA mouse model of type I diabetes. Animals are administered GNF4877 at a dose of 50 mg/kg twice per day, and blood glucose levels are measured in an oral glucose tolerance test (OGTT). The compound's ability to improve glucose tolerance is assessed in these models. |
| ADME/Pharmacokinetics |
GNF4877 has a molecular weight of 2041073-22-5. It is a potent inhibitor of DYRK1A and GSK3β. The compound is typically stored as a powder at -20°C. It is typically used for research purposes only.
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| Toxicity/Toxicokinetics |
As a research compound, its safety profile is evaluated in standard cytotoxicity and acute toxicity assays. The compound is classified for research use only and is not intended for human therapeutic use. Comprehensive toxicological characterization would be required prior to any clinical development. The compound is typically handled with standard laboratory safety precautions.
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| References | |
| Additional Infomation |
GNF4877 (CAS 2041073-22-5) is a potent dual inhibitor of DYRK1A (IC50: 6 nM) and GSK3β (IC50: 16 nM). It promotes β-cell proliferation and has been shown to reduce blood glucose in a type I diabetes model. It is not approved for clinical use and is available only for research purposes.
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| Molecular Formula |
C25H27FN6O4
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|---|---|
| Molecular Weight |
494.5181
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| Exact Mass |
494.207
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| CAS # |
2041073-22-5
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| PubChem CID |
139600315
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
760
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C([H])=C([H])C(=C([H])C=1C1=C([H])N=C(C(C(N([H])C2C([H])=NC([H])=C([H])C=2N2C([H])([H])C([H])([H])C([H])([H])[C@@]([H])(C(=O)O[H])C2([H])[H])=O)=N1)N([H])[H])OC([H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
UZIATSFXNVOVFE-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C25H27FN6O4/c1-14(2)36-16-5-6-18(26)17(10-16)19-12-29-23(27)22(30-19)24(33)31-20-11-28-8-7-21(20)32-9-3-4-15(13-32)25(34)35/h5-8,10-12,14-15H,3-4,9,13H2,1-2H3,(H2,27,29)(H,31,33)(H,34,35)/t15-/m1/s1
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| Chemical Name |
(3R)-1-[3-[[3-amino-6-(2-fluoro-5-propan-2-yloxyphenyl)pyrazine-2-carbonyl]amino]pyridin-4-yl]piperidine-3-carboxylic acid
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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: 3.33 mg/mL (6.73 mM)
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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 | 2.0222 mL | 10.1108 mL | 20.2216 mL | |
| 5 mM | 0.4044 mL | 2.0222 mL | 4.0443 mL | |
| 10 mM | 0.2022 mL | 1.0111 mL | 2.0222 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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