【作者】 王玉兰； 李林娟； 罗成； 郑明月； 蒋华良；

【Author】 Yulan Wang;Linjuan Li;Cheng Luo;Mingyue Zheng;Hualiang Jiang;Shanghai Institute of Materia Medica,Chinese Academy of Sciences;University of Chinese Academy of Sciences;School of Life Science and Technology,Shanghai Tech University;

【机构】 中国科学院上海药物研究所药物发现与设计中心； 中国科学院大学； 上海科技大学生命科学与技术学院；

【摘要】 表观遗传修饰相关的甲基转移酶在基因转录调控中发挥着重要作用,与肿瘤的发生、发展和预后密切相关,已成为抗肿瘤药物研究的重要靶点。DOT1L是一种组蛋白甲基转移酶,主要甲基化组蛋白3上的第79位赖氨酸,在MLL-重组相关白血病发生发展过程中扮演着重要的角色。本研究中,我们发展了一种甲基转移酶靶标特异性的打分函数SAM-score,并将该打分函数应用于DOT1L抑制剂筛选发现了DOT1L小分子抑制剂DCD-17。DCD-17是一类具有非核苷类骨架,对DOT1L较高抑制活性(IC50=4.5uM)和选择性的小分子抑制剂。在细胞试验中,DCD-17表现出显著的MLL-重组细胞增殖抑制活性(ED50=21.8uM)。此外,我们用分子对接模拟DCD-17及其类似物与DOT1L的结合模式,并分析了该类化合物的构效关系。本研究为研发活性更好、选择性高的DOT1L小分子抑制剂提供了重要的线索。更多还原

【Abstract】 Methyltransferases of epigenetic modification play a key role in regulating transcription and are closely related with in the genesis,development and prognosis of human cancer,which have become a promising target for cancer therapy.DOT1 L is a protein methyltransferase to methylate histone H3 on Lysine 79,which is required for the development and maintenance of MLL-rearranged mixed lineage leukemia.Here,we report the development of a target-specific score function SAM-score for S-adenosylmethionine（SAM） dependent methyltransferase targets and the discovery of novel DOTIL inhibitor DCD-17 based on SAM-score.DCD-17 is non-nucleoside DOTIL inhibitor with an IC₅₀ value of 4.5 μM and exhibits significant selectivity over other SAM-dependent methyltransferases.In cellular studies,DCD-17 inhibited MLL-rearranged cell proliferation with EC₅₀ value of 21.8 μM.Furthermore,the putative binding modes of DCD-17 and its analogs obtained by molecular docking and their structure-activity relationships were analyzed,which may assist future development DOT1 L inhibitors with better potency and selectivity profile.更多还原