An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins.
An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins.
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DOI：
10.3389/fonc.2011.00028
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发表时间：
2011
影响因子：
4.7
通讯作者：
Pellecchia M
中科院分区：
文献类型：
--
作者：
Wei J;Stebbins JL;Kitada S;Dash R;Zhai D;Placzek WJ;Wu B;Rega MF;Zhang Z;Barile E;Yang L;Dahl R;Fisher PB;Reed JC;Pellecchia M
过去几年我们的重点是鉴定新型有效的泛 Bcl-2 拮抗剂。我们最近报道了一系列 Apogossypolone (ApoG2) 衍生物，产生了手性化合物 (±) BI97D6。我们在这里报告了其光学纯（-）和（+）阻转异构体的合成和评价。化合物 (-) BI97D6 有效抑制 BH3 肽与 Bcl-XL、Bcl-2、Mcl-1 和 Bfl-1 的结合，IC50 值分别为 76±±5、31±±2、25±±8 和 122±28nM。在细胞测定中，化合物(-)BI97D6有效抑制PC-3人前列腺癌和H23人肺癌细胞系中的细胞生长，EC50值分别为0.22±0.08和0.14±0.02μM。类似地，化合物(-)BI97D6以剂量依赖性方式有效诱导BP3人淋巴瘤细胞系凋亡。该化合物对 bax−/−/bak−/− 细胞也显示出很小的细胞毒性，表明它主要通过 Bcl-2 途径杀死癌细胞。此外，化合物(-)BI97D6在Bcl-2转基因小鼠模型和小鼠前列腺癌异种移植模型中均显示出体内功效。因此，化合物(-)BI97D6代表了一种有前途的先导药物，可用于开发新型基于细胞凋亡的癌症疗法。
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.