| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
TAK1 (MAP3K7) is a key upstream kinase in the NF-kappaB and MAPK signaling pathways, activated by pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta) and TLR ligands. p38alpha (MAPK14) is a downstream effector kinase involved in stress responses and cytokine production. By inhibiting both TAK1 (IC50 = 156 nM) and p38alpha (IC50 = 186 nM), PF-05381941 blocks two critical nodes in the inflammatory signaling cascade, reducing the production of pro-inflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta.
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| ln Vitro |
PF-05381941, with an IC50 of 8 nM, suppresses the release of TNF-α from LPS-stimulated human peripheral mononuclear (PMN) cells [1].
PF-05381941 potently inhibits TAK1 kinase activity with an IC50 of 156 nM and p38alpha with an IC50 of 186 nM. In cellular assays, the compound exhibits potent suppression of TNF-alpha release from LPS-stimulated human peripheral mononuclear (PMN) cells, with an IC50 of 8 nM, demonstrating its functional efficacy in primary human immune cells. This cellular potency indicates that PF-05381941 is effective at inhibiting the inflammatory response in a physiologically relevant context. |
| ln Vivo |
Specific in vivo data for PF-05381941 are not detailed in the literature; however, as a dual TAK1/p38alpha inhibitor, it would be expected to show efficacy in animal models of inflammatory diseases such as rheumatoid arthritis (collagen-induced arthritis, CIA), inflammatory bowel disease (DSS-induced colitis), and psoriasis (imiquimod-induced model). A typical protocol would involve oral administration of the compound to mice (e.g., 10-50 mg/kg once or twice daily) to assess reduction in paw swelling, colon shortening, or skin inflammation.
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| Enzyme Assay |
The TAK1 kinase assay is performed using a recombinant TAK1-TAB1 fusion protein. The enzyme is incubated with a peptide substrate (e.g., myelin basic protein (MBP) or a specific TAK1 substrate peptide), ATP (at Km concentration), and varying concentrations of PF-05381941 in reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Tween-20). After incubation at 30degC for 60 minutes, the reaction is stopped, and the amount of phosphorylated substrate is quantified using an ADP-Glo™ luminescence assay or a radiometric method with 32P-ATP. The IC50 is calculated from the dose-response curve. A similar protocol is used for p38alpha.
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| Cell Assay |
The cellular assay is performed using human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. PBMCs are seeded in 96-well plates and pre-incubated with varying concentrations of PF-05381941 (0.1-100 nM) for 1 hour. Then, lipopolysaccharide (LPS, e.g., 1 microg/mL) is added to stimulate TLR4 signaling and induce TNF-alpha production. After 4-6 hours of incubation at 37degC, culture supernatants are collected, and TNF-alpha levels are measured by ELISA. The IC50 for TNF-alpha suppression is calculated. Alternatively, whole blood assays can be used to measure TNF-alpha release.
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| Animal Protocol |
In vivo animal experimental procedures are not detailed. A typical efficacy study would use the collagen-induced arthritis (CIA) mouse model. Female DBA/1J mice are immunized with bovine type II collagen emulsified in Freund's complete adjuvant on day 0, and boosted on day 21. PF-05381941 is administered via oral gavage at doses of 10, 30, or 100 mg/kg once or twice daily starting at the time of booster immunization. Clinical arthritis scores (paw swelling and erythema) are assessed every 2-3 days. At the end of the study (e.g., day 35-42), paws are collected for histopathological analysis, and serum is collected for cytokine measurement (TNF-alpha, IL-6, IL-1beta).
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| ADME/Pharmacokinetics |
Specific PK parameters for PF-05381941 are not detailed. However, the compound is described as a dual inhibitor of TAK1/p38alpha, and its structure (MW 466.53) suggests it could be orally bioavailable. Key PK parameters such as half-life, Cmax, AUC, and oral bioavailability would require empirical determination. The compound's ability to inhibit TNF-alpha release from PBMCs with an IC50 of 8 nM suggests it achieves adequate cellular exposure.
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| Toxicity/Toxicokinetics |
Specific toxicological data for PF-05381941 are not detailed. As an inhibitor of TAK1 and p38alpha-two critical nodes in the innate immune response-the primary on-target safety concerns would be immunosuppression and increased susceptibility to infections. p38alpha inhibitors have historically been associated with hepatotoxicity, cardiotoxicity, and gastrointestinal side effects in clinical trials, while TAK1 is essential for cellular homeostasis. Combination inhibition may have a complex safety profile, requiring careful evaluation in animal studies.
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| References | |
| Additional Infomation |
PF-05381941 is a research-grade chemical tool for studying the TAK1 and p38alpha MAPK signaling pathways. TAK1 and p38alpha are key mediators of inflammation downstream of TLRs, IL-1R, and TNF-R, and are validated targets for inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and multiple sclerosis. The compound allows researchers to investigate the effects of dual pathway inhibition, which might provide superior efficacy compared to single-target inhibition. As of the latest updates, the compound has not been approved for clinical use.
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| Molecular Formula |
C27H26N6O2
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| Molecular Weight |
466.534345149994
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| Exact Mass |
466.211
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| CAS # |
1474022-02-0
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| PubChem CID |
73212018
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| Appearance |
Off-white to brown solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
755
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=C(C=CC(OC2C=CN=CC=2)=C1C)NC(=O)NC1=CC(=NN1C1C=CC=C(C#N)C=1)C(C)(C)C
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| InChi Key |
BVCVUQMOUMAXKQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H26N6O2/c1-18-14-20(8-9-23(18)35-22-10-12-29-13-11-22)30-26(34)31-25-16-24(27(2,3)4)32-33(25)21-7-5-6-19(15-21)17-28/h5-16H,1-4H3,(H2,30,31,34)
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| Chemical Name |
1-[5-tert-butyl-2-(3-cyanophenyl)pyrazol-3-yl]-3-(3-methyl-4-pyridin-4-yloxyphenyl)urea
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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 : ~100 mg/mL (~214.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.36 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.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.36 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 1.39 mg/mL (2.98 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1435 mL | 10.7174 mL | 21.4348 mL | |
| 5 mM | 0.4287 mL | 2.1435 mL | 4.2870 mL | |
| 10 mM | 0.2143 mL | 1.0717 mL | 2.1435 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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