全新骨架组蛋白甲基转移酶G9a抑制剂的构效关系、结合模式及作用机制研究

组蛋白赖氨酸甲基转移酶G9a与肿瘤的发生发展密切相关，被认为是具有广阔前景的抗肿瘤靶标而在近年来受到广泛关注。本项目针对目前G9a小分子抑制剂的结构类型少、缺乏蛋白空腔结合模式、无体内药效学数据等问题，利用化学信息学及生物信息学手段构建形状相似形模型，发现并获得具有G9a抑制活性的全新骨架结构苗头化合物FTT-8。本项目通过分析FTT-8结构与G9a蛋白的结合模式，指导苗头化合物的结构改造及优化并进行构效关系探索，利用药物化学方法研究G9a蛋白的空腔信息以及与小分子底物之间的结合位点及结合模式，发现并获得结构新颖、活性明确的高亲和力小分子抑制剂，并以此为分子探针揭示G9a与小分子底物识别的关键药效特征，同时对活性较好的小分子进行生物机制学研究以探究G9a在肿瘤治疗领域的相关生物学信息，为后续小分子抑制剂的研究提供理论依据及参考。

Histone lysine methyltransferase G9a is considered as an anti-cancer target for its tight correlated with tumor. In order to extend the structure type of G9a inhibitor and study the binding mode between G9a protein and small molecule, ROCS model was built in our group and hit compound with moderate inhibitory activity was discovered. In this project, we will design, synthesize and bio-evaluate the molecules based on the structure of hit, then structure-activity relationship will be discussed. This project will clarify the binding mode and binding site of G9a protein with small molecule substrate and provide a reference for the next study of G9a inhibitors. Some new skeleton G9a inhibitors that deserved for further evaluation will also be obtained in this project.