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. © 2011 Wei, Stebbins, Kitada, Dash, Zhai, Placzek, Wu, Rega, Zhang, Barile, Yang, Dahl, Fisher, Reed and Pellecchia.
Wei, J., Stebbins, J. L., Kitada, S., Dash, R., Zhai, D., Placzek, W. J., … Pellecchia, M. (2011). An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic Bcl-2 family proteins. Frontiers in Oncology, 1(SEP). https://doi.org/10.3389/fonc.2011.00028