来自Baylor医学院的研究者在最新一期的PLoS One上发表研究性文章，标题为：Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation，据文章介绍一种小分子化学物质具有阻断癌基因Stat3的功能。这一研究成果对乳腺癌以及其他癌症的治疗具有指导意义。
Stat3是一个癌症基因，很多癌症患者Stat3基因的被激活直接导致癌症发生，研究人员希望能找到一种可以阻断癌基因Stat3的化学探针，他们对920,000种药物样小分子物质进行筛选，主要针对Stat3 SH2区域。SH2区域是Stat3的活性区域，在大部分的癌症患者中它具有促进恶性癌发生的功能，并能促进癌细胞转移。
通过大量的药物筛选实验，他们发现有6种小分子具有阻断Stat3的活性，其中一种名为188的小分子物质具有最强的活性。另外还有3种小分子具有诱导癌细胞系凋亡的功能。
研究者希望进行第二代药物的研究，希望能找出具有更强阻断Stat3的药物小分子。该研究受美国国立癌症研究所资助。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS ONE 4(3): e4783. doi:10.1371/journal.pone.0004783
Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation
Xuejun Xu1#, Moses M. Kasembeli1#, Xueqing Jiang1, Benjamin J. Tweardy1, David J. Tweardy1,2*
1 Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America, 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
Abstract
Signal transducer and activator of transcription (Stat) 3 is an oncogene constitutively activated in many cancer systems where it contributes to carcinogenesis. To develop chemical probes that selectively target Stat3, we virtually screened 920,000 small drug-like compounds by docking each into the peptide-binding pocket of the Stat3 SH2 domain, which consists of three sites—the pY-residue binding site, the +3 residue-binding site and a hydrophobic binding site, which served as a selectivity filter. Three compounds satisfied criteria of interaction analysis, competitively inhibited recombinant Stat3 binding to its immobilized pY-peptide ligand and inhibited IL-6-mediated tyrosine phosphorylation of Stat3. These compounds were used in a similarity screen of 2.47 million compounds, which identified 3 more compounds with similar activities. Examination of the 6 active compounds for the ability to inhibit IFN-γ-mediated Stat1 phosphorylation revealed that 5 of 6 were selective for Stat3. Molecular modeling of the SH2 domains of Stat3 and Stat1 bound to compound revealed that compound interaction with the hydrophobic binding site was the basis for selectivity. All 5 selective compounds inhibited nuclear-to-cytoplasmic translocation of Stat3, while 3 of 5 compounds induced apoptosis preferentially of breast cancer cell lines with constitutive Stat3 activation. Thus, virtual ligand screening of compound libraries that targeted the Stat3 pY-peptide binding pocket identified for the first time 3 lead compounds that competitively inhibited Stat3 binding to its pY-peptide ligand; these compounds were selective for Stat3 vs. Stat1 and induced apoptosis preferentially of breast cancer cells lines with constitutively activated Stat3.
