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

Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, Nishioka K, Nakajima T - Int. J. Mol. Med. (2012)

Bottom Line: We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

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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Effects of LS-101 and LS-102 on cell growth of RSCs. HeLa cells and RSCs derived fromtwo RA patients were treated with synoviolin inhibitors for 12 h at the indicatedconcentrations. LS-101 and LS-102 repressed the proliferation of each RSC populationtested. Data are expressed as the mean percentage of inhibition of the vehicle-treatedcontrol group ± SEM; (n=3).
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f3-ijmm-30-06-1281: Effects of LS-101 and LS-102 on cell growth of RSCs. HeLa cells and RSCs derived fromtwo RA patients were treated with synoviolin inhibitors for 12 h at the indicatedconcentrations. LS-101 and LS-102 repressed the proliferation of each RSC populationtested. Data are expressed as the mean percentage of inhibition of the vehicle-treatedcontrol group ± SEM; (n=3).

Mentions: We next tested LS-101 and LS-102 for their effects on the proliferation of RSCs, usingHeLa cells as a control. LS-101 and LS-102 inhibited HeLa cell growth only at very highconcentrations (LS-101; IC50=31.3 μM, LS-102;IC50=32.7 μM). However, treatment of RSCs with these compoundssuppressed synovial cell growth dose-dependently and with much greater potency than thatobserved in HeLa cells (Fig. 3). Asimilar effect was also observed in another line of RSCs (Fig. 3). In addition, LS-101 inhibited synovial cell proliferationmore potently than LS-102 (LS-101; IC50=4.2 μM, LS-102;IC50=5.4 μM). These results demonstrated that blockade ofsynoviolin function reduced the proliferation of RSCs, and that RSCs are more susceptibleto this effect than HeLa cells. Consistent with these findings, higher expression levelsof synoviolin were observed in RSCs than in HeLa cells (6).


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

Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, Nishioka K, Nakajima T - Int. J. Mol. Med. (2012)

Effects of LS-101 and LS-102 on cell growth of RSCs. HeLa cells and RSCs derived fromtwo RA patients were treated with synoviolin inhibitors for 12 h at the indicatedconcentrations. LS-101 and LS-102 repressed the proliferation of each RSC populationtested. Data are expressed as the mean percentage of inhibition of the vehicle-treatedcontrol group ± SEM; (n=3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042867&req=5

f3-ijmm-30-06-1281: Effects of LS-101 and LS-102 on cell growth of RSCs. HeLa cells and RSCs derived fromtwo RA patients were treated with synoviolin inhibitors for 12 h at the indicatedconcentrations. LS-101 and LS-102 repressed the proliferation of each RSC populationtested. Data are expressed as the mean percentage of inhibition of the vehicle-treatedcontrol group ± SEM; (n=3).
Mentions: We next tested LS-101 and LS-102 for their effects on the proliferation of RSCs, usingHeLa cells as a control. LS-101 and LS-102 inhibited HeLa cell growth only at very highconcentrations (LS-101; IC50=31.3 μM, LS-102;IC50=32.7 μM). However, treatment of RSCs with these compoundssuppressed synovial cell growth dose-dependently and with much greater potency than thatobserved in HeLa cells (Fig. 3). Asimilar effect was also observed in another line of RSCs (Fig. 3). In addition, LS-101 inhibited synovial cell proliferationmore potently than LS-102 (LS-101; IC50=4.2 μM, LS-102;IC50=5.4 μM). These results demonstrated that blockade ofsynoviolin function reduced the proliferation of RSCs, and that RSCs are more susceptibleto this effect than HeLa cells. Consistent with these findings, higher expression levelsof synoviolin were observed in RSCs than in HeLa cells (6).

Bottom Line: We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

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.

Show MeSH
Related in: MedlinePlus