生物素化2-甲氧基斯替潘酮的合成及其JAK2和IKK靶点的鉴定
Synthesis of Biotinylated 2-methoxystypandrone and Identification of JAK2 and IKK as its Targets.
作者信息
Kuang Shan, Sima Zhenhua, Liu Jiawei, Li Wuguo, Song Qiaoling, Zhang Qing, Yu Qiang
机构信息
Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan, Research Center of Medicinal Plants Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, China.
出版信息
Anticancer Agents Med Chem. 2018;18(3):422-427. doi: 10.2174/1871520617666171106123226.
BACKGROUND
2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-κB pathways.
OBJECTIVE
To investigate the molecular targets and mechanisms of 2-MS.
METHOD
A biotin-conjugated 2-MS analog, named 2-MS-Biotin, was designed and synthesized. The effects of 2-MS-Biotin on the STAT3 and NF-κB pathways were examined by Western blotting. The cytotoxicity of 2- MS-Biotin was evaluated using real-time cell analysis system. Proteins directly bound to 2-MS-Biotin were pulled down through streptavidin agarose beads and were detected using Western blotting.
RESULTS
2-MS-Biotin retained the inhibition activities of the parent compound 2-MS on the STAT3 and NF-κB pathways as well as on cancer cell growth. Also, JAK2 and IKK proteins can be effectively pulled down by 2- MS-Biotin.
CONCLUSION
Using 2-MS-Biotin as a tool, both JAK2 and IKK were identified as the targets of 2-MS.
背景
从虎杖根中分离出的2-甲氧基斯替潘酮（2-MS）是一种有效的信号转导和转录激活因子3（STAT3）及核因子κB（NF-κB）通路双重抑制剂。
目的
研究2-MS的分子靶点及作用机制。
方法
设计并合成一种生物素偶联的2-MS类似物，命名为2-MS-生物素。采用蛋白质免疫印迹法检测2-MS-生物素对STAT3和NF-κB通路的影响。使用实时细胞分析系统评估2-MS-生物素的细胞毒性。通过链霉亲和素琼脂糖珠拉下与2-MS-生物素直接结合的蛋白质，并采用蛋白质免疫印迹法进行检测。
结果
2-MS-生物素保留了母体化合物2-MS对STAT3和NF-κB通路以及癌细胞生长的抑制活性。此外，2-MS-生物素能有效拉下Janus激酶2（JAK2）和IκB激酶（IKK）蛋白。
结论
以2-MS-生物素为工具，确定JAK2和IKK均为2-MS的靶点。
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