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NIK SMI1 (NIK-SMI1) is a novel, highly selective and potent inhibitor of NF-κB-inducing kinase (NIK). With an IC50 of 0.23 nM, it inhibits NIK-catalyzed ATP hydrolysis to ADP.
Targets |
NIK (Ki = 0.23 nM)
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ln Vitro |
NIK SMI1 (Compound 4f) has an IC50 of 0.23±0.17 nM and blocks the NIK-catalyzed hydrolysis of ATP to ADP (fluorescence polarization, FP). With an IC50 of 34±6 nM, NIK SMI1 inhibits the expression of the NIK SMI1 response element-regulated firefly luciferase reporter gene in HEK293 cells. The nuclear translocation of p52 (RelB) is shown to be inhibited by NIK SMI1 (IC50=70 nM), as would be expected for a NIK inhibitor. NIK SMI1 has an IC50 of 373±64 nM and inhibits BAFF-induced B cell (mouse) survival in vitro[1].
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ln Vivo |
NIK SMI1 is administered orally to C57BL/6 mice twice daily for 7 days, or as a positive control, three injections of recombinant BAFF receptor fusion protein (Br3- mIgG2a) are given. The saturation of the clearance mechanisms is what causes the nonlinearity of exposure in relation to dose between 100 and 200 mg/kg. With doses of 20, 32, 18, and 7.8 mL/kg per min in the SD rat, CD-1 mouse, beagle, and cynomologous monkey, respectively, the pharmacology of NIK SMI1 is investigated. The respective volumes of distribution (Vd, L/kg) are 1.35, 1.58, 0.778, and 1.39[1].
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Cell Assay |
For the proliferation assays and the survival assays, human B cells are re-suspended in RPMI containing 2.5% and 10% FBS, respectively. For the survival and proliferation assays, mouse B cells are plated in Co-star 96-well plates at 50,000 or 150,000 cells per well. The cells are given substances (like NIK SMI1) that have been diluted in DMSO (final DMSO assay concentration=0.1%). The cells are incubated with NIK SMI1 for an hour at 37°C. After adding stimulation to the plates, survival or proliferation is assessed after four days. Cells are treated with anti-IgM (20 µg/mL), anti-rhCD40L (10 µg/mL), or anti-mouse CD40 (100 ng/mL) for the proliferation assays. For the BAFF survival assay, cells are treated with human or mouse rBAFF at 10 ng/mL, followed by Cell Titer Glo to assess survival on day four[1].
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Animal Protocol |
Mice: The C57BL/6 mice used are age-matched. These tests only make use of female mice. NIK SMI1 is administered orally in single doses of 10, 20, 60, 100, and 200 mg/kg. Animals are manually restrained before being dosed orally with a gavage needle of the proper size for PO dosing. Animals are observed for any aspiration or distress symptoms, such as lethargy, pale extremities, and abnormal breathing. For sample collection, three mice per group are tail-pricked eight times with a 27 G needle (lateral tail vein). A pre-filled costar cluster tube containing 40 μL of 1.7 mg/mL EDTA/water and 10 μL of blood is filled with the blood at each timepoint, and the tube is sealed, votexed for five seconds, and then stored on dry ice. Samples are moved to a freezer at -80°C for storage[1].
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References |
Molecular Formula |
C20H19N3O4
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Molecular Weight |
365.39
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Exact Mass |
365.1376
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Elemental Analysis |
C, 65.74; H, 5.24; N, 11.50; O, 17.51
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CAS # |
1660114-31-7
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Related CAS # |
1660114-31-7;
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Appearance |
Solid powder
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SMILES |
CN1CC[C@](C1=O)(C#CC2=CC(=CC=C2)C3=NC(=CC(=C3)OC)C(=O)N)O
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InChi Key |
LQSHXYHWYGKAMX-FQEVSTJZSA-N
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InChi Code |
InChI=1S/C20H19N3O4/c1-23-9-8-20(26,19(23)25)7-6-13-4-3-5-14(10-13)16-11-15(27-2)12-17(22-16)18(21)24/h3-5,10-12,26H,8-9H2,1-2H3,(H2,21,24)/t20-/m0/s1
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Chemical Name |
6-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-4-methoxypyridine-2-carboxamide
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Synonyms |
NIK-SMI1; NIK SMI1; NIKSMI1
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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: 73~125 mg/mL (342.1~199.8 mM)
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.84 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (6.84 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.69 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. Solubility in Formulation 4: ≥ 2.08 mg/mL (5.69 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 20.8 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. Solubility in Formulation 5: ≥ 2.08 mg/mL (5.69 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.7368 mL | 13.6840 mL | 27.3680 mL | |
5 mM | 0.5474 mL | 2.7368 mL | 5.4736 mL | |
10 mM | 0.2737 mL | 1.3684 mL | 2.7368 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.