| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 50mg |
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| Other Sizes |
| Targets |
IRAK4 (interleukin-1 receptor-associated kinase 4). Zabedosertib is a potent and selective inhibitor of IRAK4, with an IC50 of 3.4-3.55 nM. It inhibits IRAK4-mediated activation of the TLR/MYD88 pathway, preventing downstream NF-kappaB and MAPK signaling. This blocks the production of pro-inflammatory cytokines, including IL-1beta, IL-6, IL-8, and TNF-alpha, from innate immune cells such as macrophages and neutrophils.
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| ln Vitro |
In vitro, Zabedosertib inhibits IRAK4 kinase activity with an IC50 of 3.55 nM. It potently suppresses TLR4 (LPS)- and TLR7/8 (R848)-induced production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6) in human PBMCs and whole blood assays. The half-maximal inhibitory concentration (IC50) for cytokine suppression is in the low nanomolar range, and the compound is highly selective for IRAK4 over other kinases.
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| ln Vivo |
In vivo, Zabedosertib protects against LPS-induced acute respiratory distress syndrome (ARDS) and other inflammatory challenges in rodent models. Oral administration of Zabedosertib reduces lung inflammation, pulmonary edema, and pro-inflammatory cytokine levels (e.g., IL-1beta, TNF-alpha, IL-6) in bronchoalveolar lavage (BAL) fluid. It also improves survival in models of systemic inflammation (e.g., LPS-induced endotoxemia).
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| Enzyme Assay |
A biochemical kinase assay is used to measure IRAK4 inhibition: purified recombinant human IRAK4 enzyme is incubated with a peptide substrate and ATP in the presence of serially diluted Zabedosertib (e.g., 0.01-1000 nM). The phosphorylation of the substrate is measured using a luminescent or fluorescence-based detection method (e.g., ADP-Glo or time-resolved FRET). The IC50 is calculated from the dose-response curve.
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| Cell Assay |
For in vitro cellular assays, human PBMCs are isolated from healthy donors and seeded into 96-well plates. Cells are pre-incubated with serially diluted Zabedosertib (e.g., 0.1-1000 nM) for 1 hour, then stimulated with LPS (e.g., 100 ng/mL) or R848 (e.g., 1 ug/mL) for 20-24 hours. Supernatants are collected, and cytokine levels (TNF-alpha, IL-6, IL-1beta) are measured by ELISA. The IC50 for inhibition of cytokine production is calculated from the dose-response curve. Cell viability is assessed using an MTT or CellTiter-Glo assay to rule out cytotoxicity.
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| Animal Protocol |
The in vivo efficacy is evaluated in a mouse model of LPS-induced acute lung inflammation (a model of ARDS). C57BL/6 mice receive intratracheal or intranasal LPS (e.g., 5 mg/kg) to induce lung injury. Zabedosertib is administered orally at doses of 10-100 mg/kg, 1 hour before and 6 hours after LPS challenge. After 6-24 hours, BAL fluid is collected for cell counts (neutrophils, macrophages) and cytokine measurement (TNF-alpha, IL-1beta, IL-6, KC) by ELISA. Lung tissues are harvested for histopathological analysis (H&E staining) and measurement of myeloperoxidase (MPO) activity as a marker of neutrophil infiltration. In survival studies, mice are challenged with a higher dose of LPS (e.g., 20 mg/kg, i.p.), and survival is monitored for 72 hours post-LPS.
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| ADME/Pharmacokinetics |
Zabedosertib is orally bioavailable and has a molecular weight of 470.47 g/mol. Detailed in vivo PK parameters (e.g., half-life, Cmax, AUC) are available in the literature. In rodent models, the compound shows good oral exposure and a half-life supporting once- or twice-daily dosing. The solubility is 10 mM in DMSO.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies indicate that Zabedosertib is well-tolerated. No significant adverse events or organ toxicities have been reported at effective dose levels in animal models. As a small molecule IRAK4 inhibitor, the safety profile is generally favorable, with no major off-target liabilities reported.
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| References |
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| Additional Infomation |
IRAK4 kinase inhibitors
Zabedosertib is a research compound that has not been approved for therapeutic use. It was in preclinical development for inflammatory diseases, including ARDS. It is available for research purposes to study the role of IRAK4 in the TLR/MYD88 signaling pathway and to evaluate IRAK4 inhibition as a therapeutic strategy in inflammatory conditions. |
| Molecular Formula |
C20H21F3N4O4S
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|---|---|
| Molecular Weight |
470.47
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| Exact Mass |
470.123
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| CAS # |
1931994-81-8
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| PubChem CID |
121364961
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| Appearance |
White to off-white solid powder
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| Boiling Point |
620.7±55.0 °C(Predicted)
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
787
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(C1=CC2=NN(C=C2C=C1NC(=O)C3=NC(=CC=C3)C(F)(F)F)CCS(=O)(=O)C)O
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| InChi Key |
OQAMEEFUUFJZRS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H21F3N4O4S/c1-19(2,29)13-10-15-12(11-27(26-15)7-8-32(3,30)31)9-16(13)25-18(28)14-5-4-6-17(24-14)20(21,22)23/h4-6,9-11,29H,7-8H2,1-3H3,(H,25,28)
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| Chemical Name |
N-[6-(2-hydroxypropan-2-yl)-2-(2-methylsulfonylethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide
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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: 125 mg/mL (265.69 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.42 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1255 mL | 10.6277 mL | 21.2553 mL | |
| 5 mM | 0.4251 mL | 2.1255 mL | 4.2511 mL | |
| 10 mM | 0.2126 mL | 1.0628 mL | 2.1255 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05656911
Conditions:Atopic DermatitisLink: https://clinicaltrials.gov/ct2/show/NCT05003089
Conditions:Immune Mediated Inflammatory DiseasesLink: https://clinicaltrials.gov/ct2/show/NCT03493269
Conditions:Healthy Volunteers|Psoriasis
Title:Food Effect, Oral & Intravenous Pharmacokinetics and Absolute Bioavailability of BAY1834845 Including Drug-drug Interaction With Methotrexate
Status:Completed
updateDate:2019-07-15
Ctid:NCT03244462
Link: https://clinicaltrials.gov/ct2/show/NCT03244462
Conditions:InflammationLink: https://clinicaltrials.gov/ct2/show/NCT03054402
Conditions:Pelvic Inflammatory DiseaseProducts are for research use only; We do not sell to patients
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