Journal ArticleDOI
The Orally Available Spleen Tyrosine Kinase Inhibitor 2-[7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide Dihydrochloride (BAY 61-3606) Blocks Antigen-Induced Airway Inflammation in Rodents
Noriyuki Yamamoto,Keisuke Takeshita,Michitaka Shichijo,Toshio Kokubo,Masako Sato,Kosuke Nakashima,Mina Ishimori,Hiroichi Nagai,Li Yingfu,Takeshi Yura,Kevin Bacon +10 more
TLDR
It was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions and was identified as a potent and selective inhibitor of Syk kinase.Abstract:
Spleen tyrosine kinase (Syk) tyrosine kinase plays essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells; therefore, inhibitors of Syk kinase may show potential as antiasthmatic/allergic therapeutics. We identified 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride (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 and 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 receptors for Fc portion of IgG 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. Furthermore, 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.read more
Citations
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Journal ArticleDOI
Features of Selective Kinase Inhibitors
TL;DR: Some of the features that determine the cellular activity of kinase inhibitors are discussed and a framework for interpreting inhibitor selectivity is proposed.
Journal ArticleDOI
R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation
Sylvia Braselmann,Vanessa Taylor,Haoran Zhao,Su Wang,Catherine Sylvain,Muhammad Baluom,Kunbin Qu,Ellen Herlaar,Angela Lau,Chi Young,Brian R Wong,Scott Lovell,Thomas Sun,Gary Park,Ankush Argade,Stipo Jurcevic,Polly Pine,Rajinder Singh,Elliott B. Grossbard,Donald G. Payan,Esteban Masuda +20 more
TL;DR: A first-inhuman study is reported showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation and showing R406 potential for modulating Syk activity in human disease.
Journal ArticleDOI
An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma
Mirjam Kool,Monique Willart,Menno van Nimwegen,Ingrid M. Bergen,Philippe Pouliot,J. Christian Virchow,Neil C. Rogers,Fabiola Osorio,Caetano Reis e Sousa,Hamida Hammad,Bart N. Lambrecht,Bart N. Lambrecht +11 more
TL;DR: It is shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allerGEN.
Patent
Inhibitors of bruton's tyrosine kinase
TL;DR: In this article, the authors describe compounds that form covalent bonds with Bruton's tyrosine kinase (Btk) for the treatment of autoimmune diseases or conditions.
References
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Journal ArticleDOI
Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways.
Minoru Takata,H. Sabe,Akiko Hata,T. Inazu,Yukio Homma,T. Nukada,Hirohei Yamamura,Tomohiro Kurosaki +7 more
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Journal ArticleDOI
Syk tyrosine kinase required for mouse viability and B-cell development
Alec M. Cheng,Bruce Rowley,William Pao,Adrian Hayday,Joseph B. Bolen,Tony Pawson,Tony Pawson +6 more
TL;DR: Analysis of syk−/− lymphoid cells showed that the syk mutation impaired the differentiation of B-lineage cells, apparently by disrupting signalling from the pre-BCR complex and thereby preventing the clonal expansion, and further maturation, of pre-B cells.