新型STAT3小分子抑制剂的结构优化和生物学研究

项目名称： 新型STAT3小分子抑制剂的结构优化和生物学研究

项目编号： No.81473075

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李英霞

作者单位： 复旦大学

项目金额： 110万元

中文摘要： STAT3是细胞信号转导和肿瘤发生的核心调节因子，抑制STAT3-STAT3相互作用是肿瘤药物研究的热点方向，占据STAT3 SH2结构域的磷酸酪氨酸结合位点是目前抑制STAT3二聚化小分子抑制剂设计的核心，这类分子由于类药性低影响其深入的研发。我们前期靶向STAT3 SH2新的五肽结合区域，获得了具有显著抑制活性、较好选择性和类药性的STAT3小分子抑制剂Zmm-5e。现将开展如下工作：根据Zmm-5e与五肽结合区域的对接结果，进行系统的结构优化，结合分子水平活性研究结果，确证活性分子与STAT3靶蛋白的作用模式，并提高活性、选择性和类药性；开展生物学研究，阐明分子作用机制，证明用小分子占据SH2的五肽结合区域-表浅的蛋白-蛋白结合位点是抑制STAT3二聚化的一种有效新策略；开展初步成药性评价，确定先导化合物。本项目研究结果对蛋白-蛋白相互作用的小分子抑制剂的设计具有重要的指导意义。

中文关键词： 结构优化；小分子抑制剂；生物活性；药物设计；蛋白-蛋白相互作用

英文摘要： As STAT3 is a master transcriptional regulator and regulates the expression of genes involved in a variety of malignant processes, STAT3 inhibitors are currently under intense development preclinically and clinically in the oncology area. The primary molecular target has so far been the phosphotyrosine-SH2 domain interactions that stabilize active STAT3 dimers. A viable strategy to stop STAT3 dimerization is to design inhibitors blocking its SH2 domain phosphotyrosine binding site. Many of small molecule inhibitors of STAT3 are nonspecific, contain reactive groups, or are not potent in cell-based assays, therefore the search for more druggable STAT3 inhibitors with high potency and excellent bioavailability remains extremely important. By targeting pentapeptide-binding region (binding region of Phe710-Lys709-Thr708- Lys707- Leu706) of STAT3 SH2 domain we gained a novel of small molecule inhibitor of STAT3 Zmm-5e with potential inhibitory activity, better selectivity and better drugguabilty. This project is to carry out the following research work: according to molecular docking results of Zmm-5e with pentapeptide-binding region of STAT3 SH2 domain, the totally structural optimization combined with molecular biological activity results to prove the molecular binding mode with STAT3 target protein, and to improve the inhibitory activity, selectivity and drugguabilty; biological studies to insight into the molecular mechanism of action, to prove that with such a long small molecule occupying the pentapeptide-binding region of SH2 domain-superficial protein-protein binding sites on the protein surface is a new and effective strategy to inhibit STAT3-STAT3 interaction; a preliminary evaluation of druggability of active compounds to identify lead compounds. The research results of this project will not only lay the foundation for small-molecule STAT3 dimerization inhibitors, but also be of an important significance for the design of the small molecule inhibitors for other protein-protein interaction..

英文关键词： structural optimization;small molucular inhibitors;biological activity;drug design;protein-protein interaction