title: The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.
abstract: Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: He
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Selvaraju
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Curtin
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Haizhong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Comess
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Bailin
authors.initials: B
authors.lastname: Shaw
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Juliana
authors.initials: J
authors.lastname: The
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lima-Fernandes
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Szewczyk
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Cheng
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Klinge
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pliushchev
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Mikkel A
authors.initials: MA
authors.lastname: Algire
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Panchal
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Bigelow
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wu
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lindley
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Galasinski
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Buchanan
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.|eFFECTOR Therapeutics, San Diego, California, USA.
authors.forename: Gary G
authors.identifier: 0000-0003-3004-7400
authors.initials: GG
authors.lastname: Chiang
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000618737:A-395 compound; D000970:Antineoplastic Agents; C491488:EED protein, human; D007189:Indans; D013449:Sulfonamides; D063151:Polycomb Repressive Complex 2