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
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
膠原病・アレルギー・感染症内科学
|
|---|
| Research Institution | Tokyo University of Foreign Studies (T.U.F.S.) |
|---|
Principal Investigator |
INOUE Tetsufumi Tokyo University of Foreign Studies, Health Administration Center, Professor, 保健管理センター, 教授 (30092141)
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| 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)
|
|---|
| Keywords | NF-κB / Rheumatoid arthritis / IKK-β / Nuclear factor kappa B / Ikappa B kinase / 抗リウマチ薬 |
|---|
| 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.
|
Report
(3 results)
Research Products
(3 results)
