Zabedosertib (BAY 1834845) is a selective, orally active IRAK4 inhibitor with an IC50 of 3.55 nM, showing immunomodulatory potential. IRAK4 is a kinase integral to signaling innate immune responses from Toll-like receptors [1]. Zabedosertib also exhibits anti-inflammatory properties against IL-β, LPS, and Imiquimod-induced inflammation [2].
體內研究
Zabedosertib (150 mg/kg, orally, twice) mitigates lung injury and diminishes inflammation in LPS-induced ARDS in BALB/c mice [2].
Zabedosertib inhibits inflammation induced by IL-β (pO., 40-80 mg/kg, once), LPS (pO., 10-40 mg/kg, once), and Imiquimod (pO., 15-150 mg/kg, twice daily for 7 days) [3].
Zabedosertib is characterized by its pharmacokinetic profile in rats [3].
體外研究
Zabedosertib reduces the secretion of inflammatory cytokines such as IL-1, IFN-γ, TNF-α, and IL-17 at 500 nM [2].
Zabedosertib 細胞實驗
Cell Line
Concentration
Treated Time
Description
References
Human peripheral blood mononuclear cells (hPBMC)
500 nM
20 hours
Detection of the release of 48 cytokines. Both BAY-1834845 and PF-06650833 effectively reduced the secretion of inflammatory cytokines such as IL-1, IFN-γ, TNF-α, and IL-17.
Biomed Pharmacother. 2022 Sep;153:113459.
human peripheral blood mononuclear cells (hPBMC)
500 nmol/L
20 hours
To evaluate the effect of PF-06650833 on inflammatory cytokine secretion after LPS stimulation. Results showed PF-06650833 effectively reduced the secretion of inflammatory cytokines such as IL-1, IFN-γ, TNF-α, and IL-17.
Biomed Pharmacother. 2022 Sep;153:113459
Zabedosertib 動物實驗
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
IL-1β-induced inflammation model
Oral
10 and 40 mg/kg
Single dose
BAY1830839 and BAY1834845 significantly and dose-dependently reduced the levels of IL-6 and TNF-α
J Med Chem. 2024 Jan 25;67(2):1225-1242
Female Balb/c mice
LPS-induced ARDS mouse model
Oral
150 mg/kg
Preventive administration: one dose 30 min before modeling and another consolidation dose 6h later; Therapeutic administration: two doses at 4 h and 12 h after modeling.
Evaluation of the therapeutic effects of IRAK4 inhibitors on ARDS. BAY-1834845 significantly reduced lung inflammation and neutrophil infiltration, improved lung injury scores, while PF-06650833 showed minimal effects. Dexamethasone had some effects but was less significant than BAY-1834845.
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