Astemizole Arrests the Proliferation of Cancer Cells by Disrupting the EZH2-EED Interaction of Polycomb Repressive Complex 2
Astemizole Arrests the Proliferation of Cancer Cells by Disrupting the EZH2-EED Interaction of Polycomb Repressive Complex 2
复制标题
阿司咪唑通过破坏 Polycomb 抑制复合物 2 的 EZH2-EED 相互作用来阻止癌细胞增殖
DOI：
10.1021/jm501230c
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发表时间：
2014-11-27
影响因子：
7.3
通讯作者：
Luo, Cheng
中科院分区：
文献类型：
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作者：
Kong, Xiangqian;Chen, Limin;Luo, Cheng
多梳抑制复合体2 （PRC2）通过组蛋白H3 （H3K27me3）的三甲基化赖氨酸27调节染色质结构和转录抑制，这一过程需要催化亚基EZH2和EED之间的蛋白-蛋白相互作用（PPI）。不受调控的PRC2与肿瘤的发生和发展密切相关，使其成为表观遗传癌症治疗的宝贵靶点。然而，到目前为止，还没有报道过靶向EZH2-EED相互作用的小分子化合物。在本研究中，我们发现阿斯咪唑是一种fda批准的药物，可作为PRC2 EZH2-EED相互作用的小分子抑制剂。阿司咪唑破坏EZH2-EED相互作用，破坏PRC2复合物的稳定性，抑制其在癌细胞中的甲基转移酶活性。多种证据表明，阿司咪唑主要通过使PRC2复合物失能来阻止PRC2驱动的淋巴瘤的增殖。我们的研究结果证明了一种小分子化合物对复杂的PPI靶点的化学可追溯性，强调了通过靶向破坏EZH2-EED复合物治疗prc2驱动的人类癌症的前景。
Polycomb Repressive Complex 2 (PRC2) modulates the chromatin structure and transcriptional repression by trimethylation lysine 27 of histone H3 (H3K27me3), a process that necessitates the protein–protein interaction (PPI) between the catalytic subunit EZH2 and EED. Deregulated PRC2 is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. However, until now, there have been no reported small molecule compounds targeting the EZH2-EED interactions. In the present study, we identified astemizole, an FDA-approved drug, as a small molecule inhibitor of the EZH2-EED interaction of PRC2. The disruption of the EZH2-EED interaction by astemizole destabilizes the PRC2 complex and inhibits its methyltransferase activity in cancer cells. Multiple lines of evidence have demonstrated that astemizole arrests the proliferation of PRC2-driven lymphomas primarily by disabling the PRC2 complex. Our findings demonstrate the chemical tractability of the difficult PPI target by a small molecule compound, highlighting the therapeutic promise for PRC2-driven human cancers via targeted destruction of the EZH2-EED complex.