| 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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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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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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