c-Fos/AP-1 inhibitor as an intervention for the joint ...
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Kyushu University Hospital 37 c-Fos/AP-1 inhibitor as an intervention for the joint destruction in rheumatoid arthritis, the progression of systemic sclerosis, and the fatal outcome of sepsis ■ Synopsis To inhibit arthritis at the upstream of inflammatory cytokine and matrix metalloproteinase (MMP), in a de novo approach using three-dimensional (3D) pharmacophore modeling based on a 3D structure of the basic region-leucine zipper domain of AP-1–DNA complex, we designed and synthesized a small molecule c-Fos/AP-1 inhibitor. The inhibitor resolved type II collagen- induced arthritis when administered either from day 21, before onset of arthritis, or from day 27, during arthritis, with concomitant inhibition of inflammatory cytokine and MMP in vivo in sera and joints and in vitro in synovial cell and chondrocyte. Inhibition of interleukin-1β (IL-1β) and MMP was primary and direct. The selective c-Fos/AP-1 inhibitor not only resolved arthritis by primarily inhibiting IL-1β and MMP but also significantly inhibited dermal fibrosis and the fatal outcome of experimental sepsis, without significant adverse events in animals and humans. Department of Medicine, Rheumatic Disease Unit Related keywords：selective c-Fos/AP-1 inhibitor, rheumatoid arthritis, systemic sclerosis, sepsis Intellectual property information： patented Target disease: Rheumatoid arthritis, Systemic sclerosis, Sepsis
Transcript of c-Fos/AP-1 inhibitor as an intervention for the joint ...
Kyushu University Hospital Kyushu University HospitalKyushu University Hospital Kyushu University Hospital
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c-Fos/AP-1 inhibitor as an intervention for the joint destruction in rheumatoid arthritis, the progression of systemic sclerosis, and the fatal outcome of sepsis
■ SynopsisTo inhibit arthritis at the upstream of inflammatory cytokine and matrix metalloproteinase
(MMP), in a de novo approach using three-dimensional (3D) pharmacophore modeling based on a 3D structure of the basic region-leucine zipper domain of AP-1–DNA complex, we designed and synthesized a small molecule c-Fos/AP-1 inhibitor. The inhibitor resolved type II collagen-induced arthritis when administered either from day 21, before onset of arthritis, or from day 27, during arthritis, with concomitant inhibition of inflammatory cytokine and MMP in vivo in sera and joints and in vitro in synovial cell and chondrocyte. Inhibition of interleukin-1β (IL-1β) and MMP was primary and direct. The selective c-Fos/AP-1 inhibitor not only resolved arthritis by primarily inhibiting IL-1β and MMP but also significantly inhibited dermal fibrosis and the fatal outcome of experimental sepsis, without significant adverse events in animals and humans.
Department of Medicine, Rheumatic Disease Unit
Related keywords：selective c-Fos/AP-1 inhibitor, rheumatoid arthritis, systemic sclerosis, sepsis
Intellectual property information：patented
Target disease: Rheumatoid arthritis, Systemic sclerosis, Sepsis
