SUV39H2和G9a选择性可转换抑制剂的设计与合成

项目名称： SUV39H2和G9a选择性可转换抑制剂的设计与合成

项目编号： No.21302134

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 刘峰

作者单位： 苏州大学

项目金额： 25万元

中文摘要： 设计和合成以组蛋白修饰酶为靶点的化学探针，可以帮助人们深入了解"组蛋白密码"如何激活或抑制基因转录、DNA修复等生化过程以及如何影响肿瘤、神经疾病、免疫缺陷等相关疾病的形成和发展，从而进一步研发出以这些酶为靶点的新药。本项目拟以SET 结构域相近的组蛋白H3K9甲基化转移酶SUV39H2和G9a为靶点，设计并合成选择性可转换小分子抑制剂或探针,然后开展抗肿瘤活性等相关研究。通过前期的活性测试结果，我们发现有两类结构迥异的小分子均能抑制SUV39H2和G9a的活性，并且有一定的选择性；其中一类是与底物竞争的抑制剂，另一类是与辅因子SAM竞争的抑制剂。小分子和蛋白质之间相互作用的计算模拟结果显示，通过对抑制剂结构上的改造可以达到对SUV39H2和G9a抑制选择性的转换。我们将以组合化学为手段，设计和合成小分子化合物，然后根据其构效关系，进一步优化和发展出SUV39H2和G9a小分子探针。

中文关键词： 组蛋白；甲基化转移酶；高通量筛选；先导化合物；抑制剂

英文摘要： Design and synthesis of chemical probes targeting histone modification enzymes can help people to understand how "histone code" regulates the biochemical process such as transcriptional activation or repression and DNA repair and the development of diseases such as cancer, neuropathy and immunodeficiency. Based on the discovry of chemical probes,the new drugs targeting these enzymes could be developed. Considering H3K9 methyltransferases SUV39H2 and G9a with structural related SET domain, Application of the targeted design strategy to create selectivity switchable small molecule inhibitors or probes and the following research such as anti-tumor test is our proposal. According to the preliminary test results, we found two structural different small molecules which both inhibit SUV39H2 and G9a with a little selectivity. One is peptide substrate competitive inhibitor and the other one is cofactor SAM competitive inhibitor. Furthermore, The docking models of SUV39H2/G9a and the small molecules confirmed our hypothesis that it could be plausible to switch the selectivity between SUV39H2 and G9a via structural modifications of the inhibitors. By using combinatorial chemistry strategy, we will optimize the hits via iterative design, synthesis and assessment in biochemical or cellular assays to create SUV39H2 and G9a c

英文关键词： histone；methyltransferases；high-throughput screening；lead compound；inhibitor