Liang Xiaochen, Cao Yu, Duan Zhe, Wang Mingchen, Zhang Naixia, Ding Yiluan, Luo Cheng, Lu Na, Chen Shijie
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Chem. 2023 May;134:106453. doi: 10.1016/j.bioorg.2023.106453. Epub 2023 Mar 3.
Chromatin remodeling regulates many basic cellular processes, such as gene transcription, DNA repair, and programmed cell death. As the largest member of nucleosome remodeling factor (NURF), BPTF plays a vital role in the occurrence and development of cancer. Currently, BPTF bromodomain inhibitors are still in development. In this study, by conducting homogenous time-resolved fluorescence resonance energy transfer (HTRF) assay, we identified a potential, novel BPTF inhibitor scaffold Sanguinarine chloride with the IC value of 344.2 ± 25.1 nM. Biochemical analysis revealed that compound Sanguinarine chloride exhibited high binding affinity to the BPTF bromodomain. Molecular docking predicted the binding mode of Sanguinarine chloride and elucidated the activities of its derivatives. Moreover, Sanguinarine chloride showed a potent anti-proliferative effect in MIAPaCa-2 cells and inhibited the expression of BPTF target gene c-Myc. Taken together, Sanguinarine chloride provides a qualified chemical tool for developing potent BPTF bromodomain inhibitors.
染色质重塑调控许多基本的细胞过程，如基因转录、DNA修复和程序性细胞死亡。作为核小体重塑因子（NURF）的最大成员，BPTF在癌症的发生和发展中起着至关重要的作用。目前，BPTF溴结构域抑制剂仍在研发中。在本研究中，通过进行均相时间分辨荧光共振能量转移（HTRF）分析，我们鉴定出一种潜在的新型BPTF抑制剂支架——氯化血根碱，其IC值为344.2±25.1 nM。生化分析表明，化合物氯化血根碱对BPTF溴结构域表现出高结合亲和力。分子对接预测了氯化血根碱的结合模式并阐明了其衍生物的活性。此外，氯化血根碱在MIAPaCa-2细胞中显示出强大的抗增殖作用，并抑制BPTF靶基因c-Myc的表达。综上所述，氯化血根碱为开发有效的BPTF溴结构域抑制剂提供了一种合格的化学工具。
