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An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins
Our focus in the past several years has been on the identification of novel and effective pan-Bcl-2 antagonists. We have recently reported a series of Apogossypolone (ApoG2) derivatives, resulting in the chiral compound (±) BI97D6. We report here the synthesis and evaluation on its optically pure (−...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Research Foundation
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356046/ https://www.ncbi.nlm.nih.gov/pubmed/22655238 http://dx.doi.org/10.3389/fonc.2011.00028 |
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author | Wei, Jun Stebbins, John L. Kitada, Shinichi Dash, Rupesh Zhai, Dayong Placzek, William J. Wu, Bainan Rega, Michele F. Zhang, Ziming Barile, Elisa Yang, Li Dahl, Russell Fisher, Paul B. Reed, John C. Pellecchia, Maurizio |
author_facet | Wei, Jun Stebbins, John L. Kitada, Shinichi Dash, Rupesh Zhai, Dayong Placzek, William J. Wu, Bainan Rega, Michele F. Zhang, Ziming Barile, Elisa Yang, Li Dahl, Russell Fisher, Paul B. Reed, John C. Pellecchia, Maurizio |
author_sort | Wei, Jun |
collection | PubMed |
description | Our focus in the past several years has been on the identification of novel and effective pan-Bcl-2 antagonists. We have recently reported a series of Apogossypolone (ApoG2) derivatives, resulting in the chiral compound (±) BI97D6. We report here the synthesis and evaluation on its optically pure (−) and (+) atropisomers. Compound (−) BI97D6 potently inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 76 ± 5, 31 ± 2, 25 ± 8, and 122 ± 28 nM, respectively. In a cellular assay, compound (−) BI97D6 effectively inhibits cell growth in the PC-3 human prostate cancer and H23 human lung cancer cell lines with EC(50) values of 0.22 ± 0.08 and 0.14 ± 0.02 μM, respectively. Similarly, compound (−) BI97D6 effectively induces apoptosis in the BP3 human lymphoma cell line in a dose-dependent manner. The compound also shows little cytotoxicity against bax(−/−)/bak(−/−) cells, suggesting that it kills cancers cells predominantly via a Bcl-2 pathway. Moreover, compound (−) BI97D6 displays in vivo efficacy in both a Bcl-2-transgenic mouse model and in a prostate cancer xenograft model in mice. Therefore, compound (−) BI97D6 represents a promising drug lead for the development of novel apoptosis-based therapies for cancer. |
format | Online Article Text |
id | pubmed-3356046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Frontiers Research Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-33560462012-05-31 An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins Wei, Jun Stebbins, John L. Kitada, Shinichi Dash, Rupesh Zhai, Dayong Placzek, William J. Wu, Bainan Rega, Michele F. Zhang, Ziming Barile, Elisa Yang, Li Dahl, Russell Fisher, Paul B. Reed, John C. Pellecchia, Maurizio Front Oncol Oncology Our focus in the past several years has been on the identification of novel and effective pan-Bcl-2 antagonists. We have recently reported a series of Apogossypolone (ApoG2) derivatives, resulting in the chiral compound (±) BI97D6. We report here the synthesis and evaluation on its optically pure (−) and (+) atropisomers. Compound (−) BI97D6 potently inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 76 ± 5, 31 ± 2, 25 ± 8, and 122 ± 28 nM, respectively. In a cellular assay, compound (−) BI97D6 effectively inhibits cell growth in the PC-3 human prostate cancer and H23 human lung cancer cell lines with EC(50) values of 0.22 ± 0.08 and 0.14 ± 0.02 μM, respectively. Similarly, compound (−) BI97D6 effectively induces apoptosis in the BP3 human lymphoma cell line in a dose-dependent manner. The compound also shows little cytotoxicity against bax(−/−)/bak(−/−) cells, suggesting that it kills cancers cells predominantly via a Bcl-2 pathway. Moreover, compound (−) BI97D6 displays in vivo efficacy in both a Bcl-2-transgenic mouse model and in a prostate cancer xenograft model in mice. Therefore, compound (−) BI97D6 represents a promising drug lead for the development of novel apoptosis-based therapies for cancer. Frontiers Research Foundation 2011-09-30 /pmc/articles/PMC3356046/ /pubmed/22655238 http://dx.doi.org/10.3389/fonc.2011.00028 Text en Copyright © 2011 Wei, Stebbins, Kitada, Dash, Zhai, Placzek, Wu, Rega, Zhang, Barile, Yang, Dahl, Fisher, Reed and Pellecchia. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with. |
spellingShingle | Oncology Wei, Jun Stebbins, John L. Kitada, Shinichi Dash, Rupesh Zhai, Dayong Placzek, William J. Wu, Bainan Rega, Michele F. Zhang, Ziming Barile, Elisa Yang, Li Dahl, Russell Fisher, Paul B. Reed, John C. Pellecchia, Maurizio An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title | An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title_full | An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title_fullStr | An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title_full_unstemmed | An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title_short | An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins |
title_sort | optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356046/ https://www.ncbi.nlm.nih.gov/pubmed/22655238 http://dx.doi.org/10.3389/fonc.2011.00028 |
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