2004 Fiscal Year Final Research Report Summary
Inhibition of tumor necrosis factor (TNF)-α mediated IκB kinase activation in rheumatoid fibroblast-like synoviocytes in vitro and collagen-induced arthritis by a novel IKK-β inhibitor
| Project/Area Number |
15591051
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Tokyo University of Foreign Studies (T.U.F.S.) |
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Principal Investigator |
INOUE Tetsufumi Tokyo University of Foreign Studies, Health Administration Center, Professor, 保健管理センター, 教授 (30092141)
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| Co-Investigator(Kenkyū-buntansha) |
SAWADA Tetsuji The University of Tokyo, Department of Internal Medicine, Associate Professor, 附属病院, 助手 (50235470)
TUKAGOSHI Masayuki Tokyo University of Foreign Studies, Health Administration Center, Associate Professor, 保健管理センター, 助教授 (70134179)
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| Project Period (FY) |
2003 – 2004
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| Keywords | NF-κB / Rheumatoid arthritis / IKK-β |
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| Research Abstract |
Nuclear factor-κB (NF-κB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, including rheumatoid arthritis (RA). Since the majority of inflammatory signaling pathways mediated by NF-κB involve the activation of IκB kinase (IKK)-β, IKK-β is considered to be an important molecular target. The purpose of the present study was to investigate the pharmaceutical characteristics of a novel IKK-β, inhibitor, IMD-456, which was designed based on the computer-assisted drug design (CADD) program. IMD-465 was selected from a series of chemical compounds which were designed as candidates for IKK-β inhibitors by CADD technology (Institute of Molecular drug Design). The effects of IKK-b, IMD-456, on the NF-κB related function of rheumatoid fibroblast-like synoviocytes (FLS) in vitro in addition to those on the mouse collagen type II induced arthritis (CIA) model were studied beforehand. IMD-456 inhibited the proliferation of FLS, which was explained, at least in part, by the inhibitory effect on the cell cycle progression from G0/G1 to S phase, as evaluated by DNA staining. Consistently, the Codelink (DNA micro-array) analysis revealed that the mRNA levels of 335 genes, including cell-cycle relevant molecules, were decreased by treatment of RA fibroblasts with IMD-465. Thus, IMD-465, a novel anti-inflammatory compound which was designed as IKK-β inhibitor, could be a promising new tagent for RA through NF-kB inhibition.
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Research Products
(2 results)
