Naive CD4+ T helper (Th) cells can differentiate into two distinct subsets, Th2 and Th1. Th2 cells produce IL-4, IL-5, IL-10, and IL-13, and control humoral immunity against parasites and allergic reactions. Meanwhile, Th1 cells produce IFN-γ and take part in cell-mediated immunity against intracellular pathogens.
Signal transducer and activator of transcription (STAT) act as an essential transcription factor for IL-4 and IL-13 signaling. Furthermore, STAT6-deficient mice fail to develop Th2 cells. All those findings prove that STAT6 might be an excellent therapeutic target for various allergic diseases.
In this article, we will introduce a potent STAT6 inhibitor, YM-341619.
As a potent and orally active STAT6 inhibitor, YM-341619 inhibits STAT6 with an IC50 of 0.70 nM. Besides, YM-341619 inhibits IL-4-increased STAT6 luciferase gene activity in a concentration-dependent manner. The IC50 value is 1.5 nM in FW4 cells.
YM-341619 concentration-dependently decreases the production of IL-4. Additionally, YM-341619 also inhibits the expression of GATA-3 mRNA in T cells cultured with IL-4. However, it has no effects on the production of IFN-γ or the expression of T-bet (a Th1 transcription factor) mRNA in T cells with IL-12.
In a pharmacokinetic analysis in mice, after intravenous injection as a dose of 1 mg/kg. YM-341619 exhibits CLtot, t1/2, Vd values of 36.1 mL/min/kg, 1.0 hour, 3117 mL/kg, respectively. Besides, it exhibits Cmax, Tmax, AUC, and F% values of 80 ng/mL, 0.5h, 114 ng h/mL and 25%, respectively.
YM-341619 suppresses the IgE level in a dose-dependent manner, but not the IgG2a level. Additionally, the ED50 value of YM-341619 for the suppression of IgE production is 0.026 mg/kg. YM-341619 tends to decrease IL-4 production and decrease IL-13 production in a dose-dependent manner (both 57%), but does not affect IFN-γ production.
In conclusion, YM-341619 is a promising compound for the research of allergic diseases, such as allergic asthma.