Pyridone 6 (P6) delays the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6-nano strongly ameliorates atopic dermatitis (AD) in NC/Nga mice, exerting an effect comparable to that of betamethasone ointment, a commonly used drug, which also tested as a positive control. In contrast, empty polylactic acid with glycolic acid (PLGA) nanoparticles (C-nano) seemed to have no effect[2].
In Vitro
Pyridone 6 is tested as an inhibitor of 21 other protein kinases; Pyridone 6 inhibits these kinases with IC50s ranging from 130 nM to >10 μM. Pyridone 6 inhibits IL2 driven proliferation of CTLL cells with IC50=0.1 μM and IL4 driven proliferation with IC50=0.052 μM[1]. Pyridone 6 (P6) is shown to inhibit kinase by interacting within the ATP-binding cleft of each JAK. The IC50 of Pyridone 6 is 3 nM for all of these cytokines; this is comparable to the reported IC50s of Pyridone 6 for JAK2, Tyk2, and JAK3. Pyridone 6 strongly inhibits Th2 and modestly inhibits Th1, whereas it enhances Th17 development when present within a certain range of concentrations. Pyridone 6 reduces IFN-γ and IL-13, whereas it enhances IL-17 and IL-22 expression. Pyridone 6 also inhibits both Th1 and Th2 development, whereas it promotes Th17 differentiation from naive T cells when present within a certain range of concentrations[2].
Kinase Assay
Cell Assay
Naive CD4+ T cells are treated with various concentrations of Pyridone 6 (10 and 30 nM) in RPMI 1640 medium 1 h before the appropriate cytokines are added to create each Th-differentiating condition. Immunoblotting is performed using antiphospho-STAT protein Abs or anti-total STAT protein Abs[2].
Animal Administration
Mice[2] NC/Nga mice are used at the age of 10-15 wk. To assess the effect of Pyridone 6 treatment on AD symptoms, nanoparticles containing Pyridone 6 (2 mg/body) or empty nanoparticles as a negative control (C-nano) are dissolved in 0.1 mL saline and administered s.c. 1 d after Dfb ointment application; this treatment is repeated twice a week. To assess the effects of recombinant murine IL-17 and IL-22, these cytokines (50 μg/kg) or 100 μL PBS is administered for the same duration as the nanoparticles. Twenty milligrams of 0.064% betamethasone ointment are applied to the dorsal lesion of mice once a week[2].
References
[1]. Thompson JE, et al. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23.
[2]. Nakagawa R, et al. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011 Nov 1;187(9):4611-20.
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