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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/jm501230c

subject

Has Abstract

pub_date

2014-11-26 00:00:00

pages

9512-21

issue

22

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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