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Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing
Leilei Fu1, Shouyue Zhang1, Lan Zhang1,2
1State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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.
Insights
Researchers discovered BL-AD008, a novel small molecule activator targeting AMPK and ZIPK. This compound shows significant anti-proliferative effects and induces apoptosis in cervical cancer cells, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Cervical cancer remains a significant global health challenge.
- Identifying novel therapeutic targets and agents is crucial for improving treatment outcomes.
- Targeting apoptosis pathways presents a promising strategy for cancer therapy.
Purpose of the Study:
- To discover a small molecule activator targeting AMPK/ZIPK for cervical cancer therapy.
- To identify key apoptotic protein-protein interactions (PPIs) using systems biology.
- To develop a novel dual-target activator with anti-cancer properties.
Main Methods:
- Construction of a global protein-protein interaction (PPI) network.
- Prediction of apoptosis-related protein connections using a Naïve Bayesian model.
- Screening, synthesis, and characterization of small molecule compounds targeting AMPK/ZIPK.
Main Results:
- Identification of novel PPIs between apoptotic kinases, including AMPK and ZIPK.
- Discovery of BL-AD008, a novel dual-target activator of AMPK/ZIPK.
- BL-AD008 demonstrated significant anti-proliferative activity against cervical cancer cells.
- BL-AD008 induced apoptosis via death-receptor and mitochondrial pathways, modulated by AMPK and ZIPK.
- BL-AD008 exhibited anti-tumor activity and induced apoptosis by targeting AMPK/ZIPK in vivo.
Conclusions:
- Systems biology effectively identified AMPK and ZIPK as key apoptotic kinase targets.
- BL-AD008 is a novel dual-target small molecule activator with potential as an apoptosis-modulating drug for cervical cancer.
- The findings support BL-AD008 as a promising candidate for future cervical cancer therapeutic development.
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