an optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins

Clicks: 239
ID: 133421
2011
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Abstract
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.
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Authors ;Jun eWei;John L Stebbins;Shinichi eKitada;Rupesh eDash;Dayong eZhai;William J Placzek;Bainan eWu;Michele F Rega;Ziming eZhang;Elisa eBarile;Li eYang;Russell eDahl;Paul B. Fisher;John C Reed;Maurizio ePellecchia
Journal international journal of heat and technology
Year 2011
DOI
10.3389/fonc.2011.00028
URL
http://journal.frontiersin.org/Journal/10.3389/fonc.2011.00028/full
Keywords
5 Cancer apoptosis Oncology including cancer and carcinogens tumors apogossypoloneneoplasms

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