AUTHOR=Wen Mei , Deng Zhen-ke , Jiang Shi-long , Guan Yi-di , Wu Hai-zhou , Wang Xin-luan , Xiao Song-shu , Zhang Yi , Yang Jin-ming , Cao Dong-sheng , Cheng Yan 

TITLE=Identification of a Novel Bcl-2 Inhibitor by Ligand-Based Screening and Investigation of Its Anti-cancer Effect on Human Breast Cancer Cells

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00391

DOI=10.3389/fphar.2019.00391

ISSN=1663-9812

ABSTRACT=Bcl-2 family proteins are key regulators of apoptosis that is implicated in many human diseases, particularly cancer. The anti-apoptotic proteins of Bcl-2 family, such as Bcl-2, are overexpressed in numerous cancers and contribute to tumor initiation, progression and resistance to therapy. Therefore, Bcl-2 is an attractive target for drug development, and several Bcl-2 inhibitors are currently undergoing clinical trials. In this study, we carried out a QSAR-based virtual screening approach to develop potential Bcl-2 inhibitors from the SPECS database. Surface plasmon resonance (SPR) binding assay was performed to measure the interaction between Bcl-2 protein and the screened inhibitors. After that, we measured the anti-tumor activities of the 8 candidate compounds, and found that compound M1 has significant cytotoxic effect on breast cancer cells. We further proved that compound M1 downregulated Bcl-2 expression and activated apoptosis by inducing mitochondrial dysfunction. In conclusion, we identified a novel Bcl-2 inhibitor by QSAR screening, which exerted significant cytotoxic activity in breast cancer cells through inducing mitochondria-mediated apoptosis.