RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis

Yagishita,Naoko; Aratani,Satoko; Leach,Craig; Amano,Tetsuya; Yamano,Yoshihisa; Nakatani,Ko; Nishioka,Kusuki; Nakajima,Toshihiro

doi:10.3892/ijmm.2012.1129

RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis

Authors:
- Naoko Yagishita
- Satoko Aratani
- Craig Leach
- Tetsuya Amano
- Yoshihisa Yamano
- Ko Nakatani
- Kusuki Nishioka
- Toshihiro Nakajima
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Affiliations: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan, Institute of Medical Science, Tokyo Medical University, Shinjuku, Tokyo, Japan, Progenra, Inc., Malvern, PA, USA, Bayside Misato Medical Center, Kochi, Japan
Published online on: September 18, 2012 https://doi.org/10.3892/ijmm.2012.1129
Pages: 1281-1286
Copyright: © Yagishita et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

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