A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1
A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1
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DOI：
10.1002/ijc.25484
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发表时间：
2011-04
影响因子：
6.4
通讯作者：
Zhichao Zhang;T. Song;Tiantai Zhang;Jin Gao;Guiye Wu;L. An;G. Du
中科院分区：
文献类型：
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作者：
Zhichao Zhang;T. Song;Tiantai Zhang;Jin Gao;Guiye Wu;L. An;G. Du
广谱的Bc l-2小分子抑制剂作为BH3的类似物是有效的抗肿瘤药物。在这里，我们已经确定了S1，一个先前发现的小分子的Bcl-2抑制剂，是第一个真正的BH3模拟物，也是一个双重的纳米分子抑制物，对Bcl-2和Mcl-1(Ki分别为310 nM和58 nM)。荧光偏振分析、免疫共沉淀、荧光共振能量转移和shRNA检测结果表明，S1可以破坏多种细胞系中的Bcl2/Bax、Mcl-1/Bak和Bcl2/Bim异构体，激活Bax并将其转位到线粒体，激活caspase3完全依赖于Bax/Bak，进而诱导Bim非依赖性的细胞凋亡。此外，无论Mcl-1水平如何，S1均可诱导原代急性淋巴细胞白血病细胞发生凋亡。在小鼠H22(小鼠肝癌)移植瘤模型中基于机制的单剂抗肿瘤活性确定其治疗潜力。S1代表了一类新的抗肿瘤先导化合物，仅作为BH3模拟物和PAN-Bcl2抑制剂发挥作用。同时，S1可能成为研究Bcl2家族蛋白相互作用的独特工具。
Broad spectrum Bcl‐2 small molecule inhibitors act as BH3 mimetics are effective antitumor agents. Herein, we have identified S1, a previously discovered small molecule Bcl‐2 inhibitor, as the first authentic BH3 mimetic as well as a dual, nanomolar inhibitor of Bcl‐2 and Mcl‐1 (Ki = 310 nM and 58 nM, respectively). The results of fluorescence polarization assays, coimmunoprecipitation, fluorescent resonance energy transfer, and shRNA indicated that S1 can disrupt Bcl‐2/Bax, Mcl‐1/Bak and Bcl‐2/Bim heterodimerization in multiple cell lines, activate Bax accompanied by its translocation to mitochondrial, activate caspase 3 completely dependent on Bax/Bak, and in turn induce a Bim‐independent apoptosis. Moreover, S1 could induce apoptosis on the primary acute lymphoblastic leukemia cells regardless of Mcl‐1 level. Mechanism‐based single agent antitumor activity in a mouse xenograft H22 (mouse liver carcinoma) model ascertain its therapeutic potential. S1 represents a novel chemical class of antitumor leads that function solely as BH3 mimetics and pan‐Bcl‐2 inhibitors. In the meanwhile, S1 could become a unique tool for interactions between Bcl‐2 family proteins.