CCG 2046

CCG 2046是TNF-α的抑制剂，HTRF测定和ELISA测定中，IC50值分别为2.32 μM 和0.66 μM [1]。CCG 2046也是RGS4的抑制剂。

肿瘤坏死因子（TNF）家族有三个成员：TNF-α、TNF-β和LT-β，TNF-β也称为淋巴细胞毒素α，LT-α。肿瘤坏死因子α（TNF-α）是一种细胞分泌因子。它在免疫疾病和炎性疾病中起重要作用。TNF-α也参与抑制病毒复制以及程序性细胞死亡。在细胞水平上，TNF-α可以调节多个信号通路，如NF-κB的活化和细胞凋亡[1]。

LPS和TNF-α均可以下调RGS4 [2]。CCG 2046降低RGS4-Gα0相互作用信号，IC50值为4.3 ± 0.2 μM[3]。Infliximab也是TNF-α的抑制剂[4]。使用兔抗人TNF-α多克隆抗体刺激mTNF 6小时后，IL-10的 mRNA含量增加2.6倍。使用WT mTNF转染Jurkat细胞，经过10 μg/mL的infliximab培养24小时，IL-10的生成增加2.7倍，具有统计学意义。这些结果通过cDNA阵列分析表示[5]。

Infliximab输注1小时后，在一些病人血清中TNF-α蛋白的浓度显著降低。Infliximab首次剂量24小时和48小时之后，患者CCL2浓度显著下降[4]。TNF-α促进肿瘤细胞CCL2的表达[6]。

参考文献：
[1].  Leister KP, Huang R, Goodwin BL, et al. Two high throughput screen assays for measurement of TNF-α in THP-1 cells. Current chemical genomics, 2011, 5(1): 21-29.
[2].  Magder S, Neculcea J, Neculcea V, et al. Lipopolysaccharide and TNF-α produce very similar changes in gene expression in human endothelial cells. Journal of vascular research, 2006, 43(5): 447-461.
[3].  Roman DL, Talbot JN, Roof RA, et al. Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay. Molecular pharmacology, 2007, 71(1): 169-175.
[4].  Brown ER, Charles KA, Hoare SA, et al. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-α inhibitor, in patients with advanced cancer. Annals of oncology, 2008, 19(7): 1340-1346.
[5].  Mitoma H, Horiuchi T, Hatta N, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α. Gastroenterology, 2005, 128(2): 376-392.
[6].  Ben-Baruch A. Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Research, 2003, 5(1): 31-36.