| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T62431 | ||||
| Target Name | Tyrosine-protein kinase SYK | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | N-Benzyl-4-(2,5-dihydroxy-benzylamino)-benzamide | Drug Info | IC50 = 18000 nM | [526107] | |
| ELLAGIC ACID | Drug Info | IC50 = 4300 nM | [528129] | ||
| Fostamatinib | Drug Info | Ki = 30 nM | [552633] | ||
| Action against Disease Model | Fostamatinib | R788, the oral solid dosage formulation of R406, is a novel syk kinase inhibitor that blocks the activation of mast cells, B cells and macrophages by blocking IgG signaling. In the first study, R788 was found to be protective from immune thrombocytopenia and hemolytic anemia in a mouse model. This study suggests that R788 may be useful in the treatment of Immune Thrombocytopenic Purpura (ITP) as well as improving autoimmune hemolytic anemia (AIHA). In a second study, R406 inhibited t uMor growth in a dose-dependent manner in a xenograft mouse model with a h uMan acute mylelogenous leukemia (AML) FLT3 cell line, demonstrating that R406 may be a beneficial in FLT3-type AML. AML is characterized by the overproduction of immature white blood cells, which causes deficits of other normal blood cells. | Drug Info | ||
| The Effect of Target Knockout, Knockdown or Genetic Variations | Syk(-/-) bone marrow chimeras carrying a Syk-deficient hematopoietic system were generated by transplanting Syk(-/-) fetal liver cells into lethally irradiated wild-type recipients. After complete repopulation of the hematopoietic compartment, autoantibody-mediated arthritis was induced by injection of arthritogenic K/BxN ser uM. Arthritis development was monitored by macroscopic and microscopic observation of the ankle joints, micro-computed tomography of bone morphology, as well as a joint function assay.Genetic deficiency of Syk in the hematopoietic compartment completely blocked the development of all macroscopic and microscopic signs of arthritis. The Syk(-/-) mutation also prevented the appearance of periarticular bone erosions. Finally, Syk(-/-) bone marrow chimeras were completely protected from arthritis-induced loss of articular function.results indicate that Syk is critically involved in the development of all clinically relevant aspects of autoantibody-mediated K/BxN ser uM-transfer arthritis in experimental mice. These results provide the first in vivo genetic evidence of the role of Syk in the development of autoimmune arthritis. | ||||
| References | |||||
| Ref 526107 | J Med Chem. 2001 Feb 1;44(3):441-52.Design, synthesis, and biological evaluation of a series of lavendustin A analogues that inhibit EGFR and Syk tyrosine kinases, as well as tubulin polymerization. | ||||
| Ref 528129 | J Med Chem. 2006 Apr 20;49(8):2363-6.Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. | ||||
| Ref 552633 | R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008. Epub 2006 Aug 31. | ||||
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