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-核转录因子B(NF-κB，NF-κB)信号通路被认为是治疗包括类风湿关节炎(RA)在内的多种炎症性疾病的分子靶点。由于大多数由NF-κB介导的炎症信号通路都涉及IκB激酶(IβB Kinase，IKK)-β的激活，因此IKK-DNA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程序设计的新型IKK-β抑制剂IMD456的药学特性。IMD465是从分子药物设计研究所设计的一系列化合物中筛选出来的一系列IKK-β抑制剂候选化合物。除在小鼠II型胶原诱导的关节炎(CIA)模型上观察IKK-b、IMD456对体外培养的类风湿成纤维样滑膜细胞(FLS)的核因子-κB相关功能的影响外，还观察了IKK-b、IMD456对类风湿成纤维细胞样滑膜细胞相关功能的影响。抑制FLS增殖的作用至少部分是通过抑制细胞周期从G0/G1期进入S期来实现的。Codelink(DNA微阵列)分析一致地显示，IMD-465处理RA成纤维细胞后，包括细胞周期相关分子在内的335个基因的mRNA水平降低。因此，作为IKK-β抑制剂的新型抗炎化合物IMD-465可能通过抑制核因子-kB而成为治疗类风湿关节炎的新药物。

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.