Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Oncotarget
Lei-lei FuJian Huang

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 ne...Continue Reading

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Citations

Dec 19, 2016·Apoptosis : an International Journal on Programmed Cell Death·Peiqi WangLixia Chen
Feb 13, 2016·International Journal of Molecular Sciences·Zheng ShiYong Tang
Jan 27, 2016·Oncotarget·Betty Yuen Kwan LawVincent Kam Wai Wong
Nov 7, 2015·Disease Models & Mechanisms·Karen A Newell-LitwaMarcelo L Lamers

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Methods Mentioned

BETA
NMR
fluorescence microscopy
xenograft
xenografts
interaction predictions
X-ray
flow cytometry
protein assay

Software Mentioned

HomoMINT
AMBER
IntAct
BioGRID
Accelrys Discovery Studio
MMPBSA

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