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Purity: ≥98%
Adezmapimod (SB-203580; RWJ-64809; SB203580; RWJ 64809) is a novel and potent p38 mitogen-activated protein kinase inhibitor (p38MAPK inhibitor) that has the potential to treat Systemic lupus erythematosus (SLE). In THP-1 cells, it blocks PKB phosphorylation with an IC50 of 3-5 μM, inhibits p38MAPK with IC50s of 0.3-0.5 μM , and is 10-fold less potent than SAPK3(106T) and SAPK4(106T). By reducing proinflammatory cytokines and proteolytic factors in a mouse model, SB203580 inhibits the growth of endometriosis. With a Ki of 21 nM, SB203580 is a competitive ATPsite inhibitor of p38MAPK with selectivity likely influenced by nonconserved regions within or close to the ATP binding pocket.
| Targets |
p38 (IC50 = 50 nM); p38β2 (IC50 = 500 nM)
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| ln Vitro |
SB203580 has an IC50 of 3-5 μm and inhibits the proliferation of murine CT6 T cells, BAF F7 B cells, or primary human T cells when IL-2 is present. Although the concentration needed is a little bit higher and the IC50 is above 10 μm, SB203580 also inhibits IL-2-induced p70S6 kinase activation. With an IC50 in the 3-10 μm range, SB203580 also inhibits the activity of PDK1 in a dose-dependent manner.[1] SB203580 has an IC50 of about 0.07 μm for blocking p38-MAPK stimulation of MAPKAPK2, whereas it has an IC50 of 3–10 μm for blocking total SAPK/JNK activity. Higher concentrations of SB203580 cause the ERK pathway to be activated, which then improves the transcriptional activity of NF-κB.[2] Human hepatocellular carcinoma (HCC) cells are induced to undergo autophagy by SB203580.[3]
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| ln Vivo |
SB203580 protects pig myocardium in an in vivo model from ischemic damage.[4] SB203580 is effective at both preventing and treating Systemic Lupus Erythematosus (SLE) in MRL/lpr mice.[5]
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| Enzyme Assay |
Cellular receptor kinase phosphorylation assay: 4μg of sheep anti-PKBα is immobilized on 25 μL of protein G-Sepharose overnight (or 1.5 hours) and washed in Buffer A (50 mm Tris, pH 7.5, 1 mm EDTA, 1 mm EGTA, 0.5 mm Na3VO4, 0.1% β-mercaptoethanol, 1% Triton X-100, 50 mm sodium fluoride, 5 mm sodium pyrophosphate, 0.1 mm phenylmethylsulfonyl fluoride, 1 μg/mL aprotinin, pepstatin, leupeptin, and 1 μm microcystin). The immobilized anti-PKB is then incubated with 0.5 ml of the lysate (from 5 × 106 cells) for 1.5 hours, washed five times in 0.5 mL of Buffer A supplemented with 0.5 m NaCl, twice in 0.5 mL of Buffer B (50 mm Tris-HCl, pH 7.5, 0.03% (w/v) Brij-35, 0.1 mm EGTA, and 0.1% β-mercaptoethanol), and twice with 100 μl of assay dilution buffer; 5× assay dilution buffer is 100 mm MOPS, pH 7.2, 125 mm β-glycerophosphate, 25 mm EGTA, 5 mm sodium orthovanadate, 5 mm DTT. The PKB enzyme immune complex is supplemented with 10 μL of assay dilution buffer, 40 μm of protein kinase A inhibitor peptide, 100 μm of PKB-specific substrate peptide, and 10 μCi of [γ-32P]ATP. The reaction is allowed to proceed for 20 minutes at room temperature while being shaken, after which the samples are pulse spun and 40 μL of the reaction volume are transferred to another tube into which 20 μL of 40% trichloroacetic acid is added to stop the reaction. After mixing and incubating at room temperature for 5 minutes, 40 μL of the mixture is transferred onto P81 phosphocellulose paper and allowed to bind for 30 seconds. The P81 piece is cleaned in acetone at room temperature after being washed three times in 0.75% phosphoric acid. The incorporation of γ-32P is then quantified using scintillation counting.
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| Cell Assay |
In order to rest CT6 cells and BA/F3 F7 cells, they are washed three times in RPMI and cultured for an overnight period in RPMI with 5% fetal calf serum without the addition of growth factors, antibiotics, or β-mercaptoethanol. Preincubation with SB203580 or a vehicle control is carried out on 2 mL of RPMI, 5% fetal calf serum and 2–5 × 106 rested CT6 cells, as shown in the figure legends. Afterward, cells are stimulated for 5 minutes at 37 °C with 20 ng/ml recombinant human IL-2, pelleted in a minifuge for 30 seconds, the medium is aspirated, and the pellet is lysed in the proper buffer. BA/F3 cells are maintained in glutamine-containing RPMI that is additionally supplemented with 5% fetal calf serum and 0.2 μg/mL G418 and stably express deletion mutants of the IL-2 receptor β chain. The cells are then thoroughly washed, allowed to rest for the night, and then washed once more before being activated with IL-2. Such cell preparations contain >90% T cells. The incorporation of [3H]thymidine is measured in cellular proliferation assays.
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| Animal Protocol |
Systemic lupus erythematosus (SLE) are established in female MRL/lpr mice and female C57BL/6 mice
0.1 M/day Orally administered |
| References |
| Molecular Formula |
C21H16FN3OS
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|---|---|
| Molecular Weight |
377.43
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| Exact Mass |
377.10
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| Elemental Analysis |
C, 66.83; H, 4.27; F, 5.03; N, 11.13; O, 4.24; S, 8.49
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| CAS # |
152121-47-6
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| Related CAS # |
Adezmapimod hydrochloride;869185-85-3
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| Appearance |
Solid powder
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| SMILES |
CS(=O)C1=CC=C(C=C1)C2=NC(=C(N2)C3=CC=NC=C3)C4=CC=C(C=C4)F.Cl
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| InChi Key |
CDMGBJANTYXAIV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16FN3OS/c1-27(26)18-8-4-16(5-9-18)21-24-19(14-2-6-17(22)7-3-14)20(25-21)15-10-12-23-13-11-15/h2-13H,1H3,(H,24,25)
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| Chemical Name |
4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine;hydrochloride
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| Synonyms |
RWJ 64809; PB 203580; RWJ64809; SB203580; SB203580; SB 203580; RWJ-64809; PB-203580; PB203580
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.62 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 mg/mL (5.30 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 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. View More
Solubility in Formulation 3: 2 mg/mL (5.30 mM) 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; with ultrasonication. Solubility in Formulation 4: 2 mg/mL (5.30 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Solubility in Formulation 5: 4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL Solubility in Formulation 6: 16.67 mg/mL (44.17 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6495 mL | 13.2475 mL | 26.4950 mL | |
| 5 mM | 0.5299 mL | 2.6495 mL | 5.2990 mL | |
| 10 mM | 0.2649 mL | 1.3247 mL | 2.6495 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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