title: Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.
abstract: The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors: Leilei
authors: L
authors: Fu
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors: Shouyue
authors: S
authors: Zhang
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.
authors: Lan
authors: L
authors: Zhang
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors: Xupeng
authors: X
authors: Tong
authors: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.
authors: Jin
authors: J
authors: Zhang
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.|Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors: Yonghui
authors: Y
authors: Zhang
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors: Liang
authors: L
authors: Ouyang
authors: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors: Bo
authors: B
authors: Liu
authors: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.
authors: Jian
authors: J
authors: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D012097:Repressor Proteins / Q000378:metabolism*; D049490:Systems Biology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
chemical_list: D020536:Enzyme Activators; D012097:Repressor Proteins; C549924:ZGPAT protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ZIPK; apoptosis; dual-target activator (BL-AD008); systems biology network