title: An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.
abstract: Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Man
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Jeff
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Teng
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: HoMan
authors.initials: H
authors.lastname: Chan
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Zijun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Douglas
authors.initials: D
authors.lastname: Fang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fei
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Leying
authors.initials: L
authors.lastname: Feng
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Feng
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Ge
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lingel
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Fangjun
authors.initials: F
authors.lastname: Luo
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Minlong
authors.initials: M
authors.lastname: Shi
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Zhaofu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Chenhui
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authors.lastname: Zeng
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Shaolian
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Counde
authors.initials: C
authors.lastname: Oyang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: En
authors.initials: E
authors.lastname: Li
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000618736:EED226; D006657:Histones; D013450:Sulfones; D014230:Triazoles; D063151:Polycomb Repressive Complex 2; D008239:Lysine