title: 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 P. R. China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.forename: Limin
authors.initials: L
authors.lastname: Chen
authors.forename: Lianying
authors.initials: L
authors.lastname: Jiao
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.forename: Fulin
authors.initials: F
authors.lastname: Lian
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.forename: Kongkai
authors.initials: K
authors.lastname: Zhu
authors.forename: Daohai
authors.initials: D
authors.lastname: Du
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.forename: Jingshan
authors.initials: J
authors.lastname: Shen
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D016589:Astemizole / Q000737:chemistry*; D001667:Binding, Competitive; D002384:Catalysis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000737:chemistry; D006801:Humans; D008223:Lymphoma / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry*; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational
chemical_list: C491488:EED protein, human; D006657:Histones; D016589:Astemizole; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2