Chen Shijie, Li Linjuan, Chen Yantao, Hu Junchi, Liu Jingqiu, Liu Yu-Chih, Liu Rongfeng, Zhang Yuanyuan, Meng Fanwang, Zhu Kongkai, Lu Junyan, Zheng Mingyue, Chen Kaixian, Zhang Jin, Jiang Hualiang, Yao Zhiyi, Luo Cheng
School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
J Chem Inf Model. 2016 Mar 28;56(3):527-34. doi: 10.1021/acs.jcim.5b00738. Epub 2016 Mar 4.
Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 μM). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 μM in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 μM. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds.
组蛋白甲基转移酶参与许多重要的生物学过程，这些酶的异常与肿瘤发生和进展相关。端粒沉默破坏因子1样蛋白（DOT1L）是组蛋白赖氨酸甲基转移酶中的关键枢纽，据报道在混合谱系白血病（MLL）重排白血病过程中起重要作用，并已被证实是一个潜在的治疗靶点。在本研究中，我们通过基于结构的虚拟筛选与生化分析相结合，鉴定出一种新型的DOT1L抑制剂DC_L115（化学物质登记号：1163729-79-0）。这种强效抑制剂DC_L115对DOT1L表现出高抑制活性（IC50 = 1.5 μM）。通过基于表面等离子体共振的结合测定，发现DC_L115在体外以0.6 μM的结合亲和力与DOT1L结合。此外，该化合物以37.1 μM的IC50值选择性抑制MLL重排细胞的增殖。我们通过分子对接分析进一步预测了DC_L115的结合模式，发现该抑制剂竞争性占据S-腺苷甲硫氨酸的结合位点。总体而言，本研究证明了具有新型骨架的强效DOT1L抑制剂的开发。
