4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of
Janus kinase (JAK)-3. Treatment 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-dependent
leukotriene (LT) synthesis after
IgE receptor/FcepsilonRI crosslinking by >90% at low micromolar concentrations.
WHI-P97 did not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the 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 microg/kg to 50 mg/kg, and LD(10) was not reached at a 50 mg/kg dose level when administered as a single i. p. or i.v. bolus dose. Therapeutic
WHI-P97 concentrations, which inhibit mast cell
leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of
WHI-P97. Notably,
WHI-P97 showed promising
biological activity in a mouse model of allergic
asthma at nontoxic dose levels. Treatment of
ovalbumin-sensitized mice with
WHI-P97 prevented the development of
airway hyper-responsiveness to
methacholine in a dose-dependent fashion. Furthermore,
WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the
ovalbumin challenge in a dose-dependent 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.