來自Baylor醫(yī)學院的研究者在最新一期的PLoS One上發(fā)表研究性文章,，標題為：Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation,，據(jù)文章介紹一種小分子化學物質(zhì)具有阻斷癌基因Stat3的功能。這一研究成果對乳腺癌以及其他癌癥的治療具有指導意義,。
Stat3是一個癌癥基因，很多癌癥患者Stat3基因的被激活直接導致癌癥發(fā)生,，研究人員希望能找到一種可以阻斷癌基因Stat3的化學探針,，他們對920,000種藥物樣小分子物質(zhì)進行篩選，主要針對Stat3 SH2區(qū)域,。SH2區(qū)域是Stat3的活性區(qū)域,，在大部分的癌癥患者中它具有促進惡性癌發(fā)生的功能，并能促進癌細胞轉(zhuǎn)移,。
通過大量的藥物篩選實驗,，他們發(fā)現(xiàn)有6種小分子具有阻斷Stat3的活性，其中一種名為188的小分子物質(zhì)具有最強的活性,。另外還有3種小分子具有誘導癌細胞系凋亡的功能,。
研究者希望進行第二代藥物的研究，希望能找出具有更強阻斷Stat3的藥物小分子,。該研究受美國國立癌癥研究所資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
