Tyrosine Kinases as Targets for Anti-Inflammatory Therapy

Teruko      Tamura; Alexandra      Koch

doi:10.2174/187152307779939732

Abstract

Tyrosine kinases play key roles in cell proliferation, differentiation, survival, cell migration, tissue development, and cell metabolisms. Mutation and /or truncation in tyrosine kinases result in their constitutive activation independent of ligand stimulation. The constitutively activated tyrosine kinase often triggers cancer development. Furthermore, it is well documented that overexpression of tyrosine kinases is involved in malignancy. In inflammatory lesion, tyrosine kinases are also activated via over-production of growth factors and/or cytokines from tissues. Several recent studies have demonstrated that targeting tyrosine kinases in inflammatory disease may lead to an useful therapy. In this review, we describe tyrosine kinases that are or may be involved in inflammatory disease such as stem cell factor (SCF) receptor (c-Kit), platelet derived growth factor (PDGF) receptors, macrophage colony stimulating factor (M-CSF) receptor (c-Fms), Trk receptors, vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor (FGF) receptors, epidermal growth factor (EGF) receptors, macrophage stimulating protein receptor (Ron), Janus kinases (Jak), and spleen tyrosine kinase (Syk)/zeta-chain associated protein kinase of 70 kDa (ZAP-70). In addition we describe potential tools and methods that can be applied for therapy, such as small molecule kinase inhibitors, antibodies, small peptides, or truncated receptors. Since inflammatory diseases are generally complex host reactions for a long term, and tyrosine kinases are important for maintenance of cell homeostasis, a successful tyrosine kinase targeting therapy will require many further studies.

Keywords: Receptor tyrosine kinase, cytoplasmic tyrosine kinase, growth factors and cytokines, inflammatory disease, therapeutic targets, small molecule kinase inhibitors, inhibitory antibodies

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