Spleen tyrosine kinases

Spleen Tyrosine Kinase (Syk) Biology, Inhibitors and Therapeutic Applications... 

Hie synthetic routes A and B are shown schematically in Scheme 41. bSyk = spleen tyrosine kinase. 

It was shown that oral administration of curcumin (50 200 mg/kg) inhibits the development of lymphoma (SGC7901) cell-induced xenografts in nude mice [Goel et al., 2007]. Curcumin inhibited the growth of both murine and human B lymphoma cells in vitro and murine B lymphoma cells in vivo by the down-regulation of spleen tyrosine kinase (Syk) activity accompanied by the down-regulation of Akt activation [Gururajan et al., 2007]. 

Gururajan M, Dasu T, Shahidain S, Jennings CD, Robertson DA, Rangnekar VM, Bondada S. 2007. Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth. J Immunol 178 111-121. 

A series of novel 1,6-naphtyridine derivatives were prepared as potential inhibitors of human topoisomerase I (2003JMC2254), farnesyltransferase inhibitors (2003USP2003199544), p38 mitogen-activated protein kinase inhibitors (2003MI7), SYK kinase inhibitors (2003PIAW02003057695) and spleen tyrosine kinase inhibitors (2003MI8). 

Zhu Y, Herlaar E, Masuda ES, Burleson GR, Nelson AJ, Grossbard EB, Clemens GR. Immunotoxicity assessment for the novel spleen tyrosine kinase inhibitor R406. Toxicol Appl Pharmacol 2007 221 268-277. 

Sky receptor <182> [468] slow nerve growth factor receptor spleen tyrosine kinase Src64 <46> [126]... 

Spleen tyrosine kinase Allergic rhinitis, anaphylaxis, and asthma DS CATALYST Six inhibitors showed good in vitro potency [130]... 

Mazuc, E., Villoutreix, B.O., Malbec, O., Roumier, T., Fleury, S., Leonetti, J.P., Dombrowicz, D., Daeron, M., Martineau, P., and Dariavach, P. (2008) A novel dmglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally. The Journal of Allergy and Clinked Immunology, 122, 188-194. 194 el-3. 

Dasatinib, the Abl-antagonist tyrosine kinase inhibitor, suppressed adhesion-mediated respiratory burst and superoxide release of neutrophil leukocytes antagonized the leukocytes immune complex-induced activation, and their migration toward fibrinogen-coated substrate, but it did not block LPS- or TNF signaling, stimulation by zymosan, and phagocytosis. Dasatinib blocked Syk activation (spleen tyrosine kinase, agonist of Fey receptors) [2215] (Table XXVI). 

Discovery and development of spleen tyrosine kinase inhibitors 12JMC 3614. 

As it was mentioned in the previous sections, the active principle of Fostamatinib disodium (88) is Tamatinib (92), which is formed by enzymatic hydrolysis of 88 in the intestine. As in the case of lymphoma, the effect of 88 in autoimmune diseases is related to inhibition of Spleen tyrosine kinase (Syk) by 92 [241, 242]. As Syk has the central role in transmission of activating signals within B cells, inhibition of this enzyme lowers expression of a number of pro-inflammatory cytokines and hence leads to immunosuppression [243], Fostamatinib has shown significant efficacy in the treatment of patients with rheumatoid arthritis not responding to Methotrexate (272) (a drug which is used conventionally in therapy), although a number of adverse events were observed [244], If these results are confirmed once Phase III studies are completed, it may hnd a place in the treatment of patients with rheumatoid arthritis with poor response to conventional therapy (Fig. 11). 

Scott DL (2011) Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis. Drugs 71 1121-1132... 

Miller, A.L., Zhang, C., Shokat, K.M. Lowell, C.A. Generation of a novel system for studying spleen tyrosine kinase function m macrophages and B cells. J. Immunol. 182, 988-998 (2009). 

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