Yazarlar : Singh R, Masuda ES, Payan DG.

Yayın : J Med Chem.

Yayın Yılı : 2012

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/22257213

Konu : Diğer

Literatür İçeriği :  

Abstract

Spleen tyrosine kinase (SYK) is a member of the cytoplasmic protein tyrosine kinase (PTK) family and has been identified as an important target for the development of therapeutics for the treatment of allergic and autoimmune diseases. Maladies resulting from chronic inflammation and autoimmune dysfunction include, asthma, rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematosus (SLE) and idiopathic thrombocytopeniapurpura (ITP). SYK has garnered substantial attention because of its importance as a key signal transduction regulator through antigen and Fc receptors in hematopoietic cells. Recently SYK has entered the mainstream of potential pharmaceutical targets with a number of inhibitor classes being reported in the literature. The true potential as a validated target for inhibition by small molecules has been investigated in the last few years, with the emergence of advanced clinical trial data. Structurally SYK possesses a tandem N-terminal Src homology 2 domains (SH2), referred to as N-SH2 and C-SH2 domains, followed by a C-terminal kinase domain and most closely related to ZAP-70. The multiple phosphorylation sites on SYK are fundamental structural prerequisites for its diverse functional activity. Overall, these phosphorylation sites contribute to maintaining the kinase in an inactivated state. In addition, they are implicated in events leading to primary activation of the kinase catalytic domain, amplification of this activity, and the orchestrated phosphorylation of multiple substrates. Utilization of the numerous sites of phosphorylation on SYK leads to the activation of a multitude of signaling networks relevant to immune and autoimmune maladies. SYK serves as a master regulator of inflammatory responses in a multitude of immune cells and as a result, inhibiting SYK activity dampens inflammation broadly and comprehensively. The validation of SYK as an effective target for therapeutic intervention in autoimmune and inflammatory disorders has picked up pace over the last decade. In particular, this has been attributable to the recognition of key biological findings, coupled with successful small molecule inhibitors of SYK that have shown early indications of clinical efficacy in diverse autoimmune and inflammatory diseases. SYK as a target has gained reinforcement with the successful completion of several Phase 2 clinical studies in RA, ITP and B-cell lymphoma. Additional clinical studies are under way that may further emphasize the position of SYK as a therapeutically relevant target

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