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| Targets |
The primary target is nuclear factor of activated T cells 5 (NFAT5), a transcription factor that is activated by hypertonic stress and regulates the expression of pro-inflammatory cytokines and other genes. KRN2 is a selective inhibitor of NFAT5 with an IC50 of 100 nM. By inhibiting NFAT5, it reduces the expression of NFAT5 target genes, potentially attenuating inflammation and joint destruction in chronic arthritis.
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| ln Vitro |
KRN2 inhibits the expression of pro-inflammatory genes, such as Nos2 and Il6, in a selective manner, while leaving intact the high-salt-induced expression of NFAT5 and its target genes [1]. The binding of NF-κB p65 to Nfat5 promoter 1 is inhibited in a dose-dependent manner by KRN2, and the DNA binding sequence between NF-κB p65 and its Nfat5 exon 1 upstream location (base pairs -3000 to +1) is directly blocked. conversations [1].
In vitro, KRN2 is a selective inhibitor of NFAT5 with an IC50 of 100 nM. It inhibits NFAT5-mediated transcriptional activity. It has potential to treat NFAT5-mediated chronic arthritis. Specific IC50 values for other transcription factors are not widely reported. |
| ln Vivo |
KRN2 (3 mg/kg, intraperitoneal injection, once a day, for 2 weeks) can effectively block AIA in which innate immune cells play a dominant role [1]. KRN2 (3 mg/kg, intraperitoneal injection, daily) can significantly reduce CIA and AIA in mice, lowering the generation of pro-inflammatory cytokines and autoantibodies and macrophage infiltration [1].
In vivo, KRN2 is a selective NFAT5 inhibitor with potential to treat NFAT5-mediated chronic arthritis. It would be expected to reduce inflammation and joint destruction in animal models of arthritis. Typical doses and outcome measures are not widely reported. |
| Enzyme Assay |
Non-cell assays for KRN2 include NFAT5 transcriptional activity assays using an NFAT5-responsive luciferase reporter. Cells are transfected with the reporter and treated with KRN2 (0.01-10 µM). Luciferase activity is measured as a readout of NFAT5 transcriptional activity.
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| Cell Assay |
Cell-based assays for KRN2 use cells expressing NFAT5 (e.g., macrophages, synoviocytes). Cells are treated with KRN2 (0.01-10 µM) and stimulated with hypertonic stress or pro-inflammatory cytokines. NFAT5 target gene expression (e.g., TNF-α, IL-6) is measured by qRT-PCR.
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| Animal Protocol |
Animal/Disease Models: 8weeks old C57BL/6 mice were intradermally injected with 2 mg of Freund's complete adjuvant [1].
Doses: 3 mg/kg. Doses: intraperitoneal (ip) injection daily for 2 weeks Experimental Results: Effectively inhibits AIA. Animal/Disease Models: 8weeks old DBA/1J mice were immunized with bovine type II collagen [1]. Doses: 3 mg/kg. Mode of Route of Administration: Daily intraperitoneal (ip) injection. Experimental Results: Effectively inhibited CIA and AIA in mice and diminished the production of pro-inflammatory cytokines and autoantibodies as well as macrophage infiltration. In vivo, KRN2 is tested in mouse models of chronic arthritis. A typical protocol involves oral or intraperitoneal administration of KRN2 (1-30 mg/kg) in mice with collagen-induced arthritis. Arthritis severity is scored, and histological analysis of joints is performed. Inflammatory cytokine levels in serum and joints are measured by ELISA. |
| References | |
| Additional Infomation |
13-[(2-Fluorophenyl)methyl]-5,6-dihydro-9,10-dimethoxy-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium chloride is a selective inhibitor of activating T cell nuclear factor 5 (NFAT5), with an IC50 of 100 nM. KRN2 shows promise for the treatment of NFAT5-mediated chronic arthritis.
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| Molecular Weight |
479.9272
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|---|---|
| Exact Mass |
479.129
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| CAS # |
248260-75-5
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| Related CAS # |
KRN2 bromide;1390654-28-0
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| PubChem CID |
134814485
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
0
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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 |
681
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=C(C2=C[N+]3=C(C4=CC5=C(C=C4CC3)OCO5)C(=C2C=C1)CC6=CC=CC=C6F)OC.[Cl-]
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| InChi Key |
RPHFGOXVJGNJJH-UHFFFAOYSA-M
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| InChi Code |
InChI=1S/C27H23FNO4.ClH/c1-30-23-8-7-18-20(11-17-5-3-4-6-22(17)28)26-19-13-25-24(32-15-33-25)12-16(19)9-10-29(26)14-21(18)27(23)31-2;/h3-8,12-14H,9-11,15H2,1-2H3;1H/q+1;/p-1
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| Chemical Name |
21-[(2-fluorophenyl)methyl]-16,17-dimethoxy-5,7-dioxa-13-azoniapentacyclo[11.8.0.02,10.04,8.015,20]henicosa-1(13),2,4(8),9,14,16,18,20-octaene;chloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ~50 mg/mL (~104.2 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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 (5.21 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 DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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 | 2.0836 mL | 10.4182 mL | 20.8364 mL | |
| 5 mM | 0.4167 mL | 2.0836 mL | 4.1673 mL | |
| 10 mM | 0.2084 mL | 1.0418 mL | 2.0836 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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