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

核因子-κB （NF-κB）信号通路已被认为是治疗包括类风湿性关节炎（RA）在内的各种炎症性疾病的分子靶点。由于NF-κB介导的大多数炎症信号通路都涉及到IκB激酶(IKK)-β的激活，因此IKK-β被认为是一个重要的分子靶点。本研究的目的是研究基于计算机辅助药物设计（CADD）程序设计的新型IKK-β抑制剂IMD-456的药理学特性。IMD-465是通过分子药物设计研究所（Institute of Molecular drug Design）的CADD技术从一系列IKK-β抑制剂候选化合物中筛选出来的。本实验在体外研究了IKK-b、IMD-456对类风湿成纤维细胞样滑膜细胞（FLS） NF-κB相关功能的影响，并对小鼠II型胶原诱导关节炎（CIA）模型进行了研究。IMD-456抑制了FLS的增殖，至少部分原因是通过DNA染色评估，IMD-456抑制了细胞周期从G0/G1到S期的进展。Codelink （DNA微阵列）分析一致显示，使用IMD-465治疗RA成纤维细胞后，335个基因（包括细胞周期相关分子）的mRNA水平降低。因此，作为IKK-β抑制剂的新型抗炎化合物IMD-465可能通过抑制NF-kB成为治疗RA的新药物。

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.