Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer
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Leilei Fu1,*, Shouyue Zhang1,*, Lan Zhang1,2,*, Xupeng Tong1,3, Jin Zhang2, Yonghui Zhang1,4, Liang Ouyang1, Bo Liu1 and Jian Huang2
1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
3 School of Pharmacy, China Pharmaceutical University, Nanjing, China
4 Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China
* These authors contributed equally to this work
Bo Liu, email:
Jian Huang, email:
Keywords: Systems biology network, Apoptosis, AMPK, ZIPK, Dual-target activator (BL-AD008)
Received: January 16, 2015 Accepted: February 03, 2015 Published: March 10, 2015
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.
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