Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays

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• 作者：Shijie Chen ; Linjuan Li ; Yantao Chen ; Junchi Hu ; Jingqiu Liu ; Yu-Chih Liu ; Rongfeng Liu ; Yuanyuan Zhang ; Fanwang Meng ; Kongkai Zhu ; Junyan Lu ; Mingyue Zheng ; Kaixian Chen ; Jin Zhang ; Hualiang Jiang ; Zhiyi Yao ; Cheng Luo
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2016
• 出版时间：March 28, 2016
• 年：2016
• 卷：56
• 期：3
• 页码：527-534
• 全文大小：432K
• ISSN：1549-960X

文摘

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.