Autoimmune diseases, including rheumatoid arthritis (RA) and immune thrombocytopenia (ITP), are caused by aberrant immune responses. ITP is an autoimmune bleeding disorder in which opsonization by platelet-specific autoantibodies results in premature platelet destruction by macrophages. The FcγR signaling cascade has become an attractive target for treatment of RA and ITP.  Antigen-specific IgE-mediated immune responses cause allergic diseases. Targeting the FcεRI signaling pathway is a promising therapeutic option for allergic diseases. Spleen tyrosine kinase (Syk) is a nonreceptor cytoplasmic tyrosine kinase.  Sky acts downstream of immunoreceptor tyrosine-based activation motif–coupled receptors, including the B-cell receptor (BCR), Fc receptors (FcRs), and integrin signaling, and influences diverse biologic events, such as cytokine production, degranulation, differentiation, and adhesion. Thus, Syk is profoundly involved in the development of autoimmune and allergic diseases. TAS05567 is a highly selective, ATP-competitive and orally active Syk inhibitor (IC₅₀ of 0.37 nM).

TAS05567 is an ATP-competitive and orally active Syk inhibitor.

In a panel of 192 kinases, TAS05567 only shows >70% inhibition of Syk and 4 other kinases (FLT3, JAK2, KDR and RET with IC50s of 10 nM, 4.8 nM, 600 nM and 29 nM, respectively). It also Inhibits BCR-dependent signaling and FcR-dependent functions. TAS05567 suppressed both calcium flux (IC50, 27 nM) and histamine release (IC50, 13 nM) induced by crosslinking of FcεRI with IgE and antigen. Furthermore, TAS05567 suppresses the development of TRAP-positive multinucleated cells. It inhibits IgD-induced BLNK phosphorylation in mouse and rat whole blood. In addition, TAS05567 suppresses disease progression in a mouse model of collagen antibody-induced arthritis. Moreover, TAS05567 improves symptoms in a rat model of established collagen-induced arthritis.

In summary, TAS05567, a potent, selective, and orally active Syk kinase inhibitor, strongly inhibits the enzyme’s activity in IC-dependent cellular systems. TAS05567 also shows good efficacy in our animal models of RA and ITP and alleviated allergic skin inflammation in vivo. It would be an efficacious novel treatment of Ig-mediated inflammatory diseases, including RA, ITP, and type I allergic diseases.

Reference:

Hayashi H, et al. J Pharmacol Exp Ther. 2018 Jul;366(1):84-95.