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Received for publication April 2, 2003.
Revised April 9, 2003.
Accepted for publication May 20, 2003.
Syk tyrosine kinase plays essential roles in FcR- and BCR- signaling in various inflammatory cells, therefore inhibitors of Syk kinase may show potential as anti- asthmatic/allergic therapeutics. We identified BAY 61- 3606, a potent (Ki = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC50 values between 5-46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61- 3606 was highly efficacious in basophils obtained from healthy human subjects (IC50 = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50 = 8.1 nM). B cell receptor activation and FcgR signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Further, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions.
Key words:
Syk, airway inflammation, allergy, asthma, kinase inhibitor, mast cell
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