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; Yan Cheng

doi:10.3389/fphar.2019.00391

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, Yan Cheng

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Article number	391
Journal	Frontiers in Pharmacology
Volume	10
Issue number	MAR
DOIs	https://doi.org/10.3389/fphar.2019.00391
State	Published - 2019

Bibliographical note

Funding Information:
This work was supported by grants from the National Natural Science Foundation of China No. 81422051, 81402853 and 81472593, the National Key Basic Research Program (2015CB910700), the Project of Innovation-driven Plan in Central South University (502211812), and the Hunan Natural Science Foundation of China No. 2016JJ1020.

Publisher Copyright:
© 2019 Wen, Deng, Jiang, Guan, Wu, Wang, Xiao, Zhang, Yang, Cao and Cheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

Bcl-2
Breast cancer cell
QSAR
Small molecule inhibitors
Virtual screening

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fphar.2019.00391

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

abstract = "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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author = "Mei Wen and Deng, {Zhen Ke} and Jiang, {Shi Long} and Guan, {Yi Di} and Wu, {Hai Zhou} and Wang, {Xin Luan} and Xiao, {Song Shu} and Yi Zhang and Yang, {Jin Ming} and Cao, {Dong Sheng} and Yan Cheng",

note = "Funding Information: This work was supported by grants from the National Natural Science Foundation of China No. 81422051, 81402853 and 81472593, the National Key Basic Research Program (2015CB910700), the Project of Innovation-driven Plan in Central South University (502211812), and the Hunan Natural Science Foundation of China No. 2016JJ1020. Publisher Copyright: {\textcopyright} 2019 Wen, Deng, Jiang, Guan, Wu, Wang, Xiao, Zhang, Yang, Cao and Cheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.",

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AU - Jiang, Shi Long

AU - Guan, Yi Di

AU - Wu, Hai Zhou

AU - Wang, Xin Luan

AU - Xiao, Song Shu

AU - Zhang, Yi

AU - Yang, Jin Ming

AU - Cao, Dong Sheng

AU - Cheng, Yan

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PY - 2019

Y1 - 2019

N2 - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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