新型DOT1L抑制剂的构效构代关系研究

项目名称： 新型DOT1L抑制剂的构效构代关系研究

项目编号： No.81673309

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 陈越磊

作者单位： 中国科学院上海药物研究所

项目金额： 25万元

中文摘要： 组蛋白甲基化酶DOT1L是表观遗传学新靶点，其抑制剂可降低H3K79过度甲基化，防止细胞恶性增殖。已知DOT1L抑制剂主要为核苷，其中EPZ5676已进入临床一期，通过埋植微泵给药治疗MLL-r急性白血病，显示了较好的疗效及安全性。现有DOT1L抑制剂的分子活性较高，但细胞通透性、代谢稳定性和生物利用度等DMPK参数不理想，限制了其适应症开发，降低了顺应性。申请人前期研究了DOT1L抑制剂的构效关系，对前人较少研究的核苷糖片段进行了修饰，获得了一些新结构；部分化合物的细胞活性和分子活性几乎相同，超过了EPZ5676，提示细胞通透性的较大提高。基于以上工作，申请人计划以提高DOT1L抑制剂的成药性为目标，以构效构代关系研究为主线，以糖片段修饰为核心，结合前药修饰等策略，获得几个具有较好活性和DMPK参数的新型DOT1L抑制剂，为候选化合物遴选和适应症研究打下基础。

中文关键词： 构效关系；构代关系；DOT1L抑制剂；核苷；药物设计

英文摘要： DOT1L belongs to the histone methyl transferase family and is regarded as a new epigenetic therapeutic target. DOT1L inhibitors reduce hyper-methylation of H3K79 and prevent malignant proliferation of cells. Most of the current DOT1L inhibitors are nucleosides, and EPZ5676 has been advanced into Phase I clinical study. EPZ5676 demonstrated good therapeutic effect and safety profile in the treatment of MLL-r acute leukemia through continuous i.v. infusion. Current DOT1L inhibitor is a combination of good enzymatic activity and poor DMPK properties including cell permeability, metabolic stability, and bioavailability. The drawbacks limit the clinical indication of DOT1L inhibitors and decrease patient compliance. We studied the SAR of DOT1L inhibitors and solved some significant synthetic problems. Through unprecedented modification of ribose motif, we have obtained some new DOT1L inhibitors, with similar molecular and cellular activities. The significantly improved cellular activity compared to EPZ5676 indicated good cell permeability of our new compounds. On the basis of this discovery, we will further improve the drugability of new DOT1L inhibitors, by a combination of the ribose ring modification and the prodrug strategy. In this project, some new DOT1L inhibitors with improved activity and DMPK profile will be discovered. The knowledge gained in this project will support the future study of the preclinical candidate and new clinical indication targeting DOT1L.

英文关键词： Structure-activity relationship;structure-metabolism relationship;DOT1L inhibitor;Nucleoside;Drug design