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 (−...

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Main Authors:	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
Format:	Online
Language:	English
Published:	Frontiers Research Foundation 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356046/

id	pubmed-3356046
recordtype	oai_dc
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 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-XL, Bcl-2, Mcl-1, and Bfl-1 with IC50 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 EC50 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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
spellingShingle	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
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
title	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_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_sort	optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins
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-XL, Bcl-2, Mcl-1, and Bfl-1 with IC50 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 EC50 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.
publisher	Frontiers Research Foundation
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356046/
_version_	1611531189802237952

An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins

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