title: RING-finger type E3 ubiquitin ligase inhibitors as novel candidates             for the treatment of rheumatoid arthritis.
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.
authors.affiliation: Institute of Medical Science, St. Marianna University School                     of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.forename: Satoko
authors.initials: S
authors.lastname: Aratani
authors.forename: Craig
authors.initials: C
authors.lastname: Leach
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Amano
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.forename: Ko
authors.initials: K
authors.lastname: Nakatani
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005552:Forelimb / Q000187:drug effects / Q000473:pathology; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D018501:Antirheumatic Agents; D001570:Benzodiazepinones; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; C581241:LS-101; C581242:LS-102; D014227:Triazines; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases