Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2

Xiangqian Kong, Limin Chen, Lianying Jiao, Xiangrui Jiang, Fulin Lian, Junyan Lu, Kongkai Zhu, Daohai Du, Jingqiu Liu, Hong Ding, Naixia Zhang, Jingshan Shen, Mingyue Zheng, Kaixian Chen, Xin Liu, Hualiang Jiang, Cheng Luo

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)9512-9521
Number of pages10
JournalJournal of Medicinal Chemistry
Volume57
Issue number22
DOIs
StatePublished - Nov 26 2014

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kong, X., Chen, L., Jiao, L., Jiang, X., Lian, F., Lu, J., Zhu, K., Du, D., Liu, J., Ding, H., Zhang, N., Shen, J., Zheng, M., Chen, K., Liu, X., Jiang, H., & Luo, C. (2014). Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2. Journal of Medicinal Chemistry, 57(22), 9512-9521. https://doi.org/10.1021/jm501230c