Discovery of a small-molecule activator of beclin-1 that induces autophagy-associated cell death and apoptosis in triple negative breast cancer
10.16438/j.0513-4870.2021-0265
- VernacularTitle: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
- Author:
Rong-yan ZHAO
1
;
Wen-ke JIN
2
;
Xing JIANG
1
;
Zhao-xin YUAN
2
;
Bo LIU
3
;
Lei-lei FU
1
Author Information
1. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
2. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China; State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, China
3. State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, China
- Publication Type:Research Article
- Keywords:
triple negative breast cancer;
beclin-1;
small-molecule activator;
autophagy;
apoptosis
- From:
Acta Pharmaceutica Sinica
2021;56(5):1369-1383
- CountryChina
- Language:Chinese
-
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.
