Treatment of allergic asthma by targeting Janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3 ', 5 '-dibromo-4 '-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97)

4-(3',5'-Dibromo-49-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatmen t of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-d ependent leukotriene (LT) synthesis after IgE receptor/Fc epsilon RI crossl inking by >90% at low micromolar concentrations. WHI-P97 did not directly i nhibit the enzymatic activity of 5-LO, but prevented its translocation to t he nuclear membrane without affecting the requisite calcium signal. WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 mug/kg to 50 mg/kg, and LD10 was not reached at a 50 mg/kg d ose level when administered as a single i.p. or i.v. bolus dose. Therapeuti c WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administrati on of a single nontoxic 40 mg/kg bolus dose of WHI-P97. Notably, WHI-P97 sh owed promising biological activity in a mouse model of allergic asthma at n ontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 pr evented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. Furthermore, WHI-P97 inhibited the eosinophil recr uitment to the airway lumen after the ovalbumin challenge in a dose-depende nt fashion. Further development of WHI-P97 may therefore provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.