title: Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED.
abstract: Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Man
authors.initials: M
authors.lastname: Zhang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Zhao
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Feng
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Luo
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Zhenting
authors.initials: Z
authors.lastname: Gao
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Ophelia
authors.initials: O
authors.lastname: Ardayfio
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Ji-Hu
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mi
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Li
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Leying
authors.initials: L
authors.lastname: Feng
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Fangjun
authors.initials: F
authors.lastname: Luo
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Teng
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ottl
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lingel
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California, United States of America.
authors.forename: Dirksen E
authors.initials: DE
authors.lastname: Bussiere
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Chris
authors.initials: C
authors.lastname: Lu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.affiliation: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D051379:Mice; D062105:Molecular Docking Simulation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000618736:EED226; C107275:Eed protein, mouse; D004791:Enzyme Inhibitors; D013450:Sulfones; D014230:Triazoles; D063151:Polycomb Repressive Complex 2