SYK kinases

Syk kinase inhibitors which have progressed to clinical studies 387... 

The crystal structure of the tandem Src-homology 2 (SH2) domain from Syk kinase in complex with a double phosphorylated ITAM peptide has been determined at a resolution of 3 A [13]. The two adjacent Syk C-terminal and N-terminal SH2 domains are required for localization to the membrane and are fundamentally important in the activation of Syk kinase. If the interaction of the... 

In the proper cellular context in B cells, NK cells and mast cells, Syk kinase has been shown to transduce cell growth and survival signals by activating PI3K/Akt and Ras/mitogen-activated protein kinase pathways [3,46]. When deregulated, Syk activity can promote myelodysplasias, leukemogenesis, and perhaps viral-media ted cellular transformations [47,48]. By contrast, Syk has also been proposed to function as a tumor suppressor [49]. This is however, based on... 

Compound 6 inhibited Syk kinase with K = 0.01 gM, and less potently inhibited Lyn, Fyn, Src, Itk, Btk, PKCot and PKC0 with KjS = 0.75, 2.05, 5.0, >9.5, >10, >15 and >15gM, respectively, and blocked antigen presentation of IC in mouse bone marrow-derived dentritic cells [59]. Inhibition of IL4 production (EC50 = 1.08 gM) was measured to ascertain inhibition of antigen presentation of IC by dendritic cells to T cells. 

A number of other small molecule Syk kinase inhibitors have been reported in the literature [61-64], Since there are no reports of detailed evaluation or animal efficacy data, some of these inhibitors may not have advanced further. 

Poque, S.L., Kurosaki, T., Bolen, J., Herbst, R., 2000, B ceU antigen receptor-induced activation of Akt promotes B ceU survival and is dependent on Syk kinase. J. Immunol. 

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). 

Yagi, S. Suzuki, K. Hasegawa, A. Okumura, K. Ra, C. Cloning of the cDNA for the deleted syk kinase homologous to ZAP-70 from human basophilic leukemia cell line (KU812). Biochem. Biophys. Res. Commun., 200, 28-34 (1994)... 

The crystal structure of the tandem SH2 domain of the Syk kinase has also been solved in complex with a dpITAM peptide (Fiitterer et al., 1998). This structure is similar to that of Zap-70 (1) the peptide binding sites of each SH2 domain are spatially colinear so that a single dpITAM peptide bridges the two SH2 domains (2) an a-helical coiled coil links the two SH2 domains (3) the peptide and tandem SH2 domains bind... 

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