ERK Inhibitors as a Potential New Therapy for Rheumatoid Arthritis

Rheumatoid arthritis (RA), a chronic and systemic autoimmune disease that leads to progressive articular destruction, is evoked by the concerted action of RA-related cells, such as T cells, synovial fibroblasts and macrophages. Although anticytokine biologics block the intercellular signal transduction of these RA-related cells and thereby exert a strong ameliorative effect on RA, there still remains a significant percentage of nonresponsive patients. In addition to these biologics that disrupt specific intercellular signals, extracellular signal-regulated kinase (ERK) inhibitors, which are believed to target the intracellular signals common to the diverse RA-related cells, are also used as a treatment for RA patients, including those who are nonresponsive to the anticytokine therapies. Recently, potent and selective inhibitors for ERK with the co-crystal structures have been reported. FR180204, an ERK inhibitor, has been shown to be effective against mouse collagen-induced arthritis, a representative animal model of RA. This compound also suppresses the antigen-specific activation of T cells, which play a central role in the initiation and progress of the disease. Information obtained from the co-crystal structures would contribute to the improvement of the chemical characteristics. Thus, with the discovery of new potential chemical entities, ERK inhibitors may emerge as a new therapeutic approach for the treatment of RA.