药学学报, 2021, 56(5): 1369-1383
引用本文:
赵荣演, 靳文珂, 姜星, 袁兆鑫, 刘博, 符雷蕾. 靶向beclin-1小分子激动剂诱导三阴性乳腺癌细胞自噬性死亡和凋亡[J]. 药学学报, 2021, 56(5): 1369-1383.
ZHAO Rong-yan, JIN Wen-ke, JIANG Xing, YUAN Zhao-xin, LIU Bo, FU Lei-lei. Discovery of a small-molecule activator of beclin-1 that induces autophagy-associated cell death and apoptosis in triple negative breast cancer[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1369-1383.

靶向beclin-1小分子激动剂诱导三阴性乳腺癌细胞自噬性死亡和凋亡
赵荣演1, 靳文珂1,2, 姜星1, 袁兆鑫1,2, 刘博2*, 符雷蕾1*
1. 西南交通大学生命科学与工程学院, 四川 成都 610031;
2. 四川大学生物治疗国家重点实验室, 四川 成都 610041
摘要:
细胞自噬(autophagy)是一种溶酶体降解途径,在细胞内环境稳态、细胞发育、细胞免疫、抑制肿瘤、能量代谢、预防神经退行性变和延长寿命方面起着至关重要的作用。自噬的药理学激活可能是治疗癌症等某些人类疾病的有效方法。本研究基于beclin-1已有的晶体结构,联合变构位点识别方法、高通量虚拟筛选及体外活性评价,发现化合物10能激活自噬且具有良好的抗MDA-MB-231细胞增殖活性[半数抑制浓度(IC50=8.25±1.53 μmol·L-1)]。随后的分子对接、分子动力学模拟及免疫印迹研究结果表明,化合物10能够靶向激活beclin-1。体外研究表明,化合物10能够诱导MDA-MB-231细胞发生自噬相关性死亡。同时还发现化合物10激活自噬后,还伴随细胞凋亡的发生。本研究确定了候选化合物10作为开发有效的、具有选择性靶向beclin-1激活自噬的先导物,为进一步开发和优化用于临床治疗的靶向beclin-1激活自噬小分子药物提供依据。
关键词:    三阴性乳腺癌      beclin-1      小分子激动剂      自噬      凋亡     
Discovery of a small-molecule activator of beclin-1 that induces autophagy-associated cell death and apoptosis in triple negative breast cancer
ZHAO Rong-yan1, JIN Wen-ke1,2, JIANG Xing1, YUAN Zhao-xin1,2, LIU Bo2*, FU Lei-lei1*
1. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;
2. State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, China
Abstract:
Autophagy is a lysosomal degradation pathway, and plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. Here, combined with allosteric site identification methods, high-throughput virtual screening, and in vitro activity evaluation, we found that compound 10 can activate autophagy and has good anti-MDA-MB-231 cell proliferation activity (the half maximal inhibitory concentration IC50=8.25±1.53 μmol·L-1). Subsequently, molecular docking, molecular dynamics simulation, and immunoblotting assay demonstrate that compound 10 can target and activate beclin-1. In vitro studies have shown that compound 10 can induce autophagy-associated cell death in MDA-MB-231 cells. In addition, it was found that compound 10 can induce apoptosis in MDA-MB-231 cells. Taken together, we identified the candidate compound 10 as an effective and selective targeting beclin-1 to activate autophagy as a lead compound, which provide a reference for further development and optimization of small molecule drugs targeting beclin-1 to activate autophagy for clinical treatment.
Key words:    triple negative breast cancer    beclin-1    small-molecule activator    autophagy    apoptosis   
收稿日期: 2021-02-23
DOI: 10.16438/j.0513-4870.2021-0265
基金项目: 四川省应用基础研究项目(2020YJ0285).
通讯作者: 符雷蕾,Tel:15882361164,E-mail:leilei_fu@163.com;刘博,Tel:15708469925,E-mail:liubo2400@163.com
Email: leilei_fu@163.com;liubo2400@163.com
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