An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment

Meltzer, Eli O.; Berkowitz, Ruth; Grossbard, Elliott B.

doi:10.1016/j.jaci.2005.01.040

Cited by 140 publications

(100 citation statements)

References 10 publications

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“…A Syk tyrosine kinase inhibitor, R112, which disrupts mast cell IgE-FceRI signaling has displayed promising results in recent clinical trials and may represent a new class of allergy therapeutics [149,150]. MAPKs are also well-recognized mediators of mast cell activation, survival, differentiation and cytokine production.…”

Section: Intracellular Targetsmentioning

confidence: 99%

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Brown

Wilson

Metcalfe

2007

Clin Experimental Allergy

239

184

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SummaryMast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FceRI) and upon aggregation of FceRI by allergen-specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.

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Section: Intracellular Targetsmentioning

confidence: 99%

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Brown

Wilson

Metcalfe

2007

Clin Experimental Allergy

239

184

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“…R112, çoklu doz güvenlik testlerinden geçtikten sonra, 319 mevsimsel alerjik rinit hastalarında 2 gün çift kör plasebo-kontrollü klinik çalışmaları yapılmıştır. R112, tüm klinik semptomlarda önemli bir azalma sağlamış olup, alerjik rinitin akut semptomlarının düzeltilmesinde Dtk inhibisyonunun klinik öne-mini ortaya koymuştur (58).…”

Section: Dtk'nin İnhibitörleriunclassified

Signal Transduction of Zymosan and Spleen Tyrosine Kinase

Ünsal¹,

Temiz²,

Tunçtan³

et al. 2014

MUSBED

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Zimosan sinyal iletisi ve dalak tirozin kinazıZimosan, Saccharomyces cerevisiae'nin hücre duvarından elde edilen, polisakkarit zincirlerinden oluşan bir bileşendir. Zimosan, başlıca 1,3-β-glukan, 1,6-β-glukan ve α-mannan gibi çapraz bağlı polisakkaritlerden oluşmaktadır. Zimosan, fungal sepsis, septik olmayan şok, çoklu organ yetmezliği, akut peritonit, irritabl bağırsak sendromu gibi enflamatuvar hastalıkların patojenezinde rol oynamakta ve ilgili deneysel modellerde kullanılmaktadır. Zimosanın monosit, makrofaj ve dendritik hücreler gibi immün sistem hücrelerindeki etkilerine toll-like receptor 2, dektin-1, mannoz ve kompleman reseptörleri gibi çeşitli reseptörler aracılık etmektedir. Dalak tirozin kinazı (Dtk), 72 kDa ağırlığında reseptör ile kenetli olmayan bir intraselüler tirozin kinazdır. Dtk'nin, mast hücreleri, nötrofiller, makrofajlar ve trombositler gibi tüm hematopoetik hücrelerde ve fibroblastlar, epitel, sinir ve damar endotel hücreleri gibi hematopoetik olmayan hücrelerde eksprese edildiği gösterilmiştir. Dtk, zimosanın dektin-1 reseptörü aracılığıyla oluşturduğu hücresel yanıtlara aracılık eden önemli bir kinazdır. Bu derlemede, zimosan sinyal iletisinde Dtk'nin rolü değerlendirilmiştir. Anahtar sözcükler: Zimosan, Dalak tirozin kinazı, dektin-1, enflamasyon ABS TRACT Signal transduction of zymosan and spleen tyrosine kinaseZymosan is a component produced by polysaccharide which is obtained from cell wall of Saccharomyces cerevisiae. Zymosan consists of crosslinked polysaccharides such as 1,3-β glucan, 1,6-β glucan, and α-mannan. Zymosan plays a role in inflammmatory diseases such as fungal sepsis, non-septic shock, multiple organ dysfunction syndrome, acute peritonitis, irritable bowel syndrome and it is used in related experimental models. Toll-like receptor 2, dectin-1, mannose, and compleman receptors mediate zymosan's effects on immune system cells such as monocytes, macrophages, and dendritic cells. Spleen tyrosine kinase (Syk) is a cytosolic, intracellular, 72-kDa protein tyrosine kinase. It is demonstrated that Syk is expressed in hematopoietic cells such as mast cells, neutrophils, macrophages, B cells, leukocytes, and platelets and in non-hematopoietic cells such as epithelial, fibroblast, neuronal cells, and vascular endothelial cells. Spleen tyrosine kinase is a critical kinase that mediates cellular responses through dectin-1 receptor by zymosan. In this review, the role of syk in is evaluated in the signal transduction of zymosan.

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“…Anti-sense approaches to knockdown Syk expression have also suppressed airway inflammation in rat asthma models, as well as antigen-induced contraction of isolated tracheas (Stenton et al, 2002). Finally, the Syk inhibitor, R-112, has also been shown to improve symptoms of seasonal allergic rhinitis (Meltzer, Berkowitz, & Grossbard, 2005). An alternative compound, R-343, has completed phase I clinical trials for asthma and phase II trials are being planned (Norman, 2009).…”

Section: Syk Inhibitorsmentioning

confidence: 99%