Zimlovisertib (PF-06650833) is a potent, selective, and orally bioavailable inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), showing IC50 values of 0.2 nM in cell assays and 2.4 nM in peripheral blood mononuclear cell (PBMC) assays. It is primarily aimed at treating conditions such as rheumatoid arthritis, lupus, and lymphomas[1].[2].
体内研究
Oral administration of Zimlovisertib (0.3-30 mg/kg) to male Sprague-Dawley rats significantly suppressed LPS-induced TNF-α production in a dose-dependent manner. Plasma concentrations of Zimlovisertib were measured at 2.1 nM, 7.7 nM, 19 nM, and 150 nM free, respectively, 2.5 hours post-administration at the aforementioned dosages. The fraction of Zimlovisertib unbound in rat plasma was determined to be 0.3[1].
体外研究
In a kinome profiling study involving 278 kinases at a concentration of 200 nM, Zimlovisertib exhibited near-total inhibition of IRAK4 activity[1].
Zimlovisertib's specificity was further evaluated in a whole cell functional VEGF2R assay using the PAE-KDR cell line, where it showed no activity at concentrations up to 30 μM. Additionally, at 100 μM, Zimlovisertib was found to inhibit the hERG current by 25% in a voltage clamp assay[1].
Investigations into Zimlovisertib's effect on major CYP450 enzymes, using pooled human liver microsomes and specific probe substrates, indicated less than 5% inhibition of CYPs 1A2, 2C8, 2C9, 2D6, and 3A4 at 3 μM. Moreover, no time-dependent inhibition of these enzymes was observed even at 100 μM. Zimlovisertib, at 10 μM, led to a 4.4-fold increase in CYP3A mRNA in cryopreserved human hepatocytes, suggesting potential induction effects[1].
Zimlovisertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human peripheral blood mononuclear cells (hPBMC)
500 nmol/L
20 hours
To evaluate the effect of PF-06650833 on cytokine secretion after LPS stimulation. Results showed that 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.
T cells
20 μM
96 hours
To evaluate the effect of PF-06650833 on T cell proliferation and IFN-γ production, results showed that PF-06650833 significantly suppressed IFN-γ production by T cells without affecting their proliferation.
Haematologica. 2020 Jan;105(1):226-234.
Zimlovisertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Λ-carrageenan-induced paw edema and DSS-induced ulcerative colitis
Intravenous injection
23 mg/kg
Every other day for a total of four injections
To evaluate the accumulation and anti-inflammatory effects of VCAM1-targeted nanocarriers in inflamed tissues. Results demonstrated that VCAM1-targeted nanocarriers significantly reduced paw edema and colitis symptoms, decreased proinflammatory cytokine levels in affected tissues, and showed no apparent systemic toxicity.
Small. 2024 Jan;20(4):e2306270
Female Balb/c mice
Inhaled lipopolysaccharide (LPS)-induced ARDS mouse model
Oral
100 mg/kg
Preventive administration: one dose 30 min before modeling and another dose 6h after modeling; Therapeutic administration: two doses at 4 h and 12 h after modeling.
To evaluate the therapeutic effect of PF-06650833 in the ARDS model. Results showed that although PF-06650833 exhibited excellent IRAK4 inhibitory activity in vitro, it failed to significantly alleviate lung injury or reduce inflammatory cell infiltration in the in vivo model.
Biomed Pharmacother. 2022 Sep;153:113459.
Mice
Graft-versus-host disease model
Intravenous injection
12.0 mg/kg
Once daily for 20 days
To evaluate the effect of PF-06650833 on graft-versus-host disease, results showed that PF-06650833 significantly ameliorated morbidity and mortality of GvHD.
Evaluate the inhibitory effect of PF-06650833 on AZ617-induced human TNFα, significantly reducing circulating human TNFα
J Biol Methods. 2023 Nov 20;10:jbm-10-e99010008
Balb/c mice
Inhaled LPS-induced ARDS mouse model
Oral
100 mg/kg
Preventive administration: single dose 30 min before modeling; Therapeutic administration: twice at 4 h and 12 h after LPS modeling
To evaluate the therapeutic effect of PF-06650833 in ARDS model. Results showed PF-06650833 failed to significantly improve lung injury scores and inflammatory cell infiltration, performing worse compared to BAY-1834845.
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