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 

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

JOURNAL=Frontiers in Oncology

VOLUME=1

YEAR=2011

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2011.00028

DOI=10.3389/fonc.2011.00028

ISSN=2234-943X

ABSTRACT=<p>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<sub>L</sub>, Bcl-2, Mcl-1, and Bfl-1 with IC<sub>50</sub> 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<sub>50</sub> 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 <italic>bax</italic><sup>−<italic>/</italic>−</sup>/<italic>bak</italic><sup>−<italic>/</italic>−</sup> cells, suggesting that it kills cancers cells predominantly via a Bcl-2 pathway. Moreover, compound (−) BI97D6 displays <italic>in vivo</italic> 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.</p>