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。
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 IC_(50) 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 EC_(50) 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.
引文
[1]Daigle,S.R.;Olhava,E.J.;Therkelsen,C.A.et al.Blood 2013,122:1017-1025.
[2]Xue,M.;Zheng,M.;Xiong,B.et al.J.Chem.Inf.Model 2010,50:1378-86.