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].
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