Ikeda Kentaro, Kamisuki Shinji, Uetake Shoko, Mizusawa Akihito, Ota Nozomi, Sasaki Tatsuki, Tsukuda Senko, Kusayanagi Tomoe, Takakusagi Yoichi, Morohashi Kengo, Yamori Takao, Dan Shingo, Shiina Isamu, Sugawara Fumio
Department of Applied Biological Science, Tokyo University of Science, Chiba, Japan.
Department of Applied Chemistry, Tokyo University of Science, Tokyo, Japan.
Bioorg Med Chem. 2015 Sep 15;23(18):6118-24. doi: 10.1016/j.bmc.2015.08.001. Epub 2015 Aug 5.
Ridaifen-G (RID-G), a tamoxifen analog that we previously synthesized, has potent growth inhibitory activity against various cancer cell lines. Tamoxifen is an anticancer drug known to act on an estrogen receptor (ER) and other proteins. However, our previous studies interestingly suggested that the mechanism of action of RID-G was different from that of tamoxifen. In order to investigate the molecular mode of action of RID-G, we developed a novel chemical genetic approach that combined a phage display screen with a statistical analysis of drug potency and gene expression profiles in thirty-nine cancer cell lines. Application of this method to RID-G revealed that three proteins, calmodulin (CaM), heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), and zinc finger protein 638 (ZNF638) were the candidates of direct targets of RID-G. Moreover, cell lines susceptible to RID-G show similar expression profiles of RID-G target genes. These results suggest that RID-G involves CaM, hnRNP A2/B1, and ZNF638 in its growth inhibitory activity.
瑞达芬 - G（RID - G）是我们之前合成的一种他莫昔芬类似物，对多种癌细胞系具有强大的生长抑制活性。他莫昔芬是一种已知作用于雌激素受体（ER）和其他蛋白质的抗癌药物。然而，我们之前的研究有趣地表明，RID - G的作用机制与他莫昔芬不同。为了研究RID - G的分子作用模式，我们开发了一种新颖的化学遗传学方法，该方法将噬菌体展示筛选与对39种癌细胞系中药物效力和基因表达谱的统计分析相结合。将此方法应用于RID - G发现，三种蛋白质，即钙调蛋白（CaM）、异质性核糖核蛋白A2/B1（hnRNP A2/B1）和锌指蛋白638（ZNF638）是RID - G直接靶点的候选蛋白。此外，对RID - G敏感的细胞系显示出类似的RID - G靶基因表达谱。这些结果表明，RID - G在其生长抑制活性中涉及CaM、hnRNP A2/B1和ZNF638。
