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

作者：Mei Wen, Zhen‐Ke Deng, Shilong Jiang, Yidi Guan, Hai-zhou Wu, Xinluan Wang, Songshu Xiao, Yi Zhang, Jinming Yang, Dongsheng Cao, Yan Cheng · 发表于：Frontiers in Pharmacology · 年份：2019 · DOI：10.3389/fphar.2019.00391 · 被引用次数：17 · 研究领域：Computational Drug Discovery Methods、Synthesis and biological activity、Bioactive Compounds and Antitumor Agents

Bcl-2 family protein is an important factor in regulating apoptosis and is associated with cancer. The anti-apoptotic proteins of Bcl-2 family, such as Bcl-2, are overexpression in numerous tumors, and contribute to cancer formation, development, and therapy resistance. Therefore, Bcl-2 is a promising 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 examine 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.