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

Aikawa, Yukihiko, Morimoto, Kimiko, Yamamoto, Tetsuya, Chaki, Hisaaki, Hashiramoto, Akira, Narita, Hirokazu, Hirono, Shuichi, Shiozawa, Shunichi·2008·Nature Biotechnology
DOI 10.1038/nbt1412
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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 1beta; this molecule also synergized with anti-tumor necrosis factor alpha to inhibit arthritis. Thus, selective inhibition of c-Fos/AP-1 resolves arthritis in a preclinical model of the disease.

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  • The selective AP-1 inhibitor T-5224 impaired TAC-induced expression of TERT.

    “A selective AP-1 inhibitor T-5224 that specifically blocks FOS/AP-1 binding to DNA without affecting their expression23 impaired TAC-induced expression of TERT (Figures 2K and S2C).”

    From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [23]

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Metadata

Authors
Aikawa, Y., Morimoto, K., Yamamoto, T., Chaki, H., Hashiramoto, A., Narita, H., Hirono, S., & Shiozawa, S.
Venue
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Published
2008-06-29
Volume
26
Issue
7
Pages
817-823
ISSN
  • 1087-0156
  • 1546-1696
DOI
10.1038/nbt1412
Cited by
214
References
1
Language
en
Licence
www.springer.com/tdm (tdm)

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