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

• Published in: Frontiers in pharmacology Vol. 10; p. 391
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.04.2019
• Subjects: Bcl-2; breast cancer cell; Pharmacology; QSAR; small molecule inhibitors; virtual screening; Bcl-2; small molecule inhibitors; virtual screening; QSAR; breast cancer cell
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2019.00391

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.