title: Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.
abstract: Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai 201203,  China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.forename: HoMan
authors.initials: H
authors.lastname: Chan
authors.forename: Lin
authors.initials: L
authors.lastname: Teng
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Zhang
authors.forename: Jue
authors.initials: J
authors.lastname: Zeng
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.forename: Ophelia
authors.initials: O
authors.lastname: Ardayfio
authors.forename: Ji-Hu
authors.initials: JH
authors.lastname: Zhang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yan
authors.forename: Jialuo
authors.initials: J
authors.lastname: Fang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mi
authors.forename: Man
authors.initials: M
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Grace
authors.initials: G
authors.lastname: Feng
authors.forename: Zijun
authors.initials: Z
authors.lastname: Chen
authors.forename: Guobin
authors.initials: G
authors.lastname: Li
authors.forename: Teddy
authors.initials: T
authors.lastname: Yang
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.forename: Xianghui
authors.initials: X
authors.lastname: Liu
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
authors.forename: Chris X
authors.initials: CX
authors.lastname: Lu
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: En
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D054852:Small Molecule Libraries; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2