title: Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer.
abstract: The aim of this study was to explore the autophagy-related protein 4B(ATG4B) and its targeted candidate agonist in triple-negative breast cancer (TNBC) therapy. In this study, the identification of Atg4B as a novel breast cancer target for screening candidate small molecular agonists was performed by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro, MTT assay, electron microscopy, western blot and ROS measurement were used for validating the efficacy of the candidate compounds. We used the phylogenetic analysis of Atg4B and constructed their protein-protein interaction (PPI) network. Also, we screened target compounds of Atg4 proteins from Drugbank and ZINC. Flubendazole was validated for its anti-proliferative efficacy in MDA-MB-231 cells. Further MD simulation results supported the stable interaction between Flubendazole and Atg4B. Moreover, Flubendazole induced autophagy and increased ROS production. In conclusion, in silico analysis and experimental validation together demonstrate that Flubendazole can target Atg4B in MDA-MB-231 cells and induce autophagy, which may shed light on the exploration of this compound as a potential new Atg4B targeted drug for future TNBC therapy.
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China. liubo2400@163.com.
authors: Lan
authors: L
authors: Zhang
authors: Mingrui
authors: M
authors: Guo
authors: Jing
authors: J
authors: Li
authors: Yaxin
authors: Y
authors: Zheng
authors: Shouyue
authors: S
authors: Zhang
authors: Tao
authors: T
authors: Xie
authors: Bo
authors: B
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins; D001943:Breast Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010802:Phylogeny; D025941:Protein Interaction Mapping; D017382:Reactive Oxygen Species / Q000378:metabolism; D054852:Small Molecule Libraries / Q000032:analysis / Q000494:pharmacology; D049490:Systems Biology / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D000071183:Autophagy-Related Proteins; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D008463:Mebendazole; C507524:ATG4B protein, human; D003546:Cysteine Endopeptidases; C018945:flubendazole