Frontiers in Pharmacology (Apr 2019)

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

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

DOI
https://doi.org/10.3389/fphar.2019.00391
Journal volume & issue
Vol. 10

Abstract

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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.

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