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Rigel, of South San Francisco, California, is positioning R788 (tamatinib fodium), an inhibitor of Syk kinase, as a direct challenger to the tumor necrosis factor-alpha (TNF-α) inhibitor biologics. A safe and effective oral drug would threaten several multibillion-dollar biologic franchises, not only in rheumatoid arthritis but also in several other autoimmune conditions, including Crohn's disease and psoriasis (see Table 1). An oral inhibitor would not only have delivery advantages over TNF-α inhibitors, which require injection, but also might have an improved side effect profile compared with biologics, which can cause fulminant opportunistic infections.
R788 is a prodrug of R406, an inhibitor of a cytoplasmic (or 'non–membrane associated') tyrosine kinase known as spleen tyrosine kinase, or Syk. Although the human gene encoding the enzyme was cloned and characterized in 1994, its role in normal—and aberrant—immune signaling has become apparent only recently. Syk is responsible for the intracellular propagation of activation signals that are triggered by the binding of the Fc region of an antibody at extracellular Fc receptors in macrophages, neutrophils and mast cells, and by the binding of antigens at extracellular B-cell receptors in B cells. (Clin. Immunol.124, 235–237, 2007). The enzyme also affects signaling in osteoclasts, which are responsible for much of the bone destruction in rheumatoid arthritis. “It seems like it affects all the partners that are involved,” says George Tsokos, professor of medicine and chief of the rheumatology division at Harvard Medical School in Boston. His group, which has had a minor collaboration with Rigel, has unpublished data indicating that inhibiting Syk corrects aberrant T-cell signaling in systemic lupus erythematosus (SLE).