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

Abstract

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.

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Figure 1: Structure and function of T-5224.
Figure 2: Effect of T-5224 on type II collagen–induced arthritis in DBA/1J mice (CIA).
Figure 3: Therapeutic use of T-5224.
Figure 4: Mechanism of action of T-5224.

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Acknowledgements

We thank Marc Lamphier, Yasushi Miura and Ken Tsumiyama, Kobe University, for useful discussion. This research was supported by the grants from the Contract Development Program of Japan Science and Technology Agency and 21st Century COE Program 'Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as a Model' from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.S.).

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Y.A., K.M., T.Y. and A.H. did animal and molecular biology experiments. H.C. and H.N. did the work on chemical compounds. S.H. did work on computer-aided drug design. S.S. organized the design and experiments of the study.

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Correspondence to Shunichi Shiozawa.

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Competing interests

Several of the authors (Y.A., K.M., T.Y., H.C., H.N.) are or have been employees of Toyama Chemical Co., Ltd.

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Figures 1–3, Table 1, Methods (PDF 1530 kb)

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Aikawa, Y., Morimoto, K., Yamamoto, T. et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol 26, 817–823 (2008). https://doi.org/10.1038/nbt1412

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