| Summary: | 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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