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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 in vitro ubiquitination. (A) BothLS-101 and LS-102 inhibited the autoubiquitination of synoviolin in a dose-dependentmanner. The IC50 of LS-101 was 20 μM and that of LS-102 was 35μM. (B) Selectivity of LS-101 (left) and LS-102 (right) against other E3ubiquitin ligases. LS-102 inhibited synoviolin selectively compared with LS-101. Dataare mean ± SEM of 3 experiments.
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f2-ijmm-30-06-1281: Effects of LS-101 and LS-102 on in vitro ubiquitination. (A) BothLS-101 and LS-102 inhibited the autoubiquitination of synoviolin in a dose-dependentmanner. The IC50 of LS-101 was 20 μM and that of LS-102 was 35μM. (B) Selectivity of LS-101 (left) and LS-102 (right) against other E3ubiquitin ligases. LS-102 inhibited synoviolin selectively compared with LS-101. Dataare mean ± SEM of 3 experiments.

Mentions: Further evaluation of LS-101 and LS-102 in an in vitro ubiquitinationassay showed that the inhibition of synoviolin activity by both LS-101 and LS-102 wasdose-dependent (LS-101; IC50=20 μM, LS-102;IC50=35 μM) (Fig.2A). To assess the selectivity of the compounds for other E3 ubiquitin ligases,we determined the effects of LS-101 and LS-102 on the enzymatic activity of the followingRING-finger type E3 ubiquitin ligases: ariadne, Drosophila, homolog of, 1(ARIH1) (19), breast cancer 1 gene(BRCA1)/BRCA1-associated RING domain 1 (BARD1) (20), and estrogen-responsive RING-finger protein (Efp) (21). LS-101 inhibited the activity ofBRCA1/BARD1 and Efp (Fig. 2B),although this effect was weaker than that observed with synoviolin (Fig. 2B). Moreover, LS-101 had no effectagainst the enzymatic activity of ARIH1 (Fig. 2B). On the other hand, LS-102 did not inhibit the activity of other E3ubiquitin ligases, only affecting synoviolin (Fig. 2B). These results suggested that LS-102 is a more selectivesynoviolin inhibitor than LS-101.


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 in vitro ubiquitination. (A) BothLS-101 and LS-102 inhibited the autoubiquitination of synoviolin in a dose-dependentmanner. The IC50 of LS-101 was 20 μM and that of LS-102 was 35μM. (B) Selectivity of LS-101 (left) and LS-102 (right) against other E3ubiquitin ligases. LS-102 inhibited synoviolin selectively compared with LS-101. Dataare mean ± SEM of 3 experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ijmm-30-06-1281: Effects of LS-101 and LS-102 on in vitro ubiquitination. (A) BothLS-101 and LS-102 inhibited the autoubiquitination of synoviolin in a dose-dependentmanner. The IC50 of LS-101 was 20 μM and that of LS-102 was 35μM. (B) Selectivity of LS-101 (left) and LS-102 (right) against other E3ubiquitin ligases. LS-102 inhibited synoviolin selectively compared with LS-101. Dataare mean ± SEM of 3 experiments.
Mentions: Further evaluation of LS-101 and LS-102 in an in vitro ubiquitinationassay showed that the inhibition of synoviolin activity by both LS-101 and LS-102 wasdose-dependent (LS-101; IC50=20 μM, LS-102;IC50=35 μM) (Fig.2A). To assess the selectivity of the compounds for other E3 ubiquitin ligases,we determined the effects of LS-101 and LS-102 on the enzymatic activity of the followingRING-finger type E3 ubiquitin ligases: ariadne, Drosophila, homolog of, 1(ARIH1) (19), breast cancer 1 gene(BRCA1)/BRCA1-associated RING domain 1 (BARD1) (20), and estrogen-responsive RING-finger protein (Efp) (21). LS-101 inhibited the activity ofBRCA1/BARD1 and Efp (Fig. 2B),although this effect was weaker than that observed with synoviolin (Fig. 2B). Moreover, LS-101 had no effectagainst the enzymatic activity of ARIH1 (Fig. 2B). On the other hand, LS-102 did not inhibit the activity of other E3ubiquitin ligases, only affecting synoviolin (Fig. 2B). These results suggested that LS-102 is a more selectivesynoviolin inhibitor than LS-101.

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