Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1

Therapies that target only one inflammatory cytokine such as tumor necrosis factor α are often insufficient to treat rheumatoid arthritis. Aikawa et al . show that a small molecule targeting c-Fos/AP-1, a transcription factor that regulates both inflammatory cytokines and matrix metalloproteinases, inhibits type II collagen-induced arthritis in mice. To inhibit arthritis upstream of inflammatory cytokine release and matrix metalloproteinase (MMP) action, we designed de novo a small-molecule inhibitor of c-Fos/activator protein-1 (AP-1) using three-dimensional (3D) pharmacophore modeling. This model was based on the 3D structure of the basic region–leucine zipper domain of AP-1–DNA complex. Administration of this inhibitor prevented type II collagen–induced arthritis from day 21, before the onset of arthritis, or from day 27, resolved arthritis after its onset. Suppression of disease was accomplished by reducing the amounts of inflammatory cytokines and MMPs in vivo in sera and joints and in vitro in synovial cell and chondrocyte cultures. The primary action of this molecule was the inhibition of matrix-degrading MMPs and inflammatory cytokines including interleukin 1β; this molecule also synergized with anti-tumor necrosis factor α to inhibit arthritis. Thus, selective inhibition of c-Fos/AP-1 resolves arthritis in a preclinical model of the disease.