Shao Zhiyuan, Xu Pan, Xu Wen, Li Linjuan, Liu Shien, Zhang Rukang, Liu Yu-Chih, Zhang Chenhua, Chen Shijie, Luo Cheng
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem Lett. 2017 Jan 15;27(2):342-346. doi: 10.1016/j.bmcl.2016.11.023. Epub 2016 Nov 11.
DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC values of 46.5μM and 41μM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.
DNA甲基转移酶参与多种生物学过程，异常的甲基化模式在癌症的发生和发展中起着至关重要的作用。作为一种从头DNA甲基转移酶的DNA甲基转移酶3A（DNMT3A），尤其在血液系统疾病中受到广泛关注。迄今为止，已经发现了大量的DNA甲基转移酶抑制剂，然而，靶向DNMT3A的小分子抑制剂仍处于起步阶段。在本研究中，进行了基于结构的虚拟筛选并结合生物学试验以发现有效的新型DNMT3A抑制剂。化合物40和40_3对DNMT3A显示出相当的体外抑制活性，IC值分别为46.5μM和41μM。进一步的结合模式分析表明，这些分子通过结合S-腺苷-L-甲硫氨酸（SAM）口袋来抑制DNMT3A活性。总体而言，40和40_3可作为进一步优化的新型骨架以及用于研究DNMT3A功能的小分子探针。
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