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The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.
He, Yupeng; Selvaraju, Sujatha; Curtin, Michael L; Jakob, Clarissa G; Zhu, Haizhong; Comess, Kenneth M; Shaw, Bailin; The, Juliana; Lima-Fernandes, Evelyne; Szewczyk, Magdalena M; Cheng, Dong; Klinge, Kelly L; Li, Huan-Qiu; Pliushchev, Marina; Algire, Mikkel A; Maag, David; Guo, Jun; Dietrich, Justin; Panchal, Sanjay C; Petros, Andrew M; Sweis, Ramzi F; Torrent, Maricel; Bigelow, Lance J; Senisterra, Guillermo; Li, Fengling; Kennedy, Steven; Wu, Qin; Osterling, Donald J; Lindley, David J; Gao, Wenqing; Galasinski, Scott; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Buchanan, Fritz G; Arrowsmith, Cheryl H; Chiang, Gary G; Sun, Chaohong; Pappano, William N.
Afiliación
  • He Y; AbbVie Inc., North Chicago, Illinois, USA.
  • Selvaraju S; AbbVie Inc., North Chicago, Illinois, USA.
  • Curtin ML; AbbVie Inc., North Chicago, Illinois, USA.
  • Jakob CG; AbbVie Inc., North Chicago, Illinois, USA.
  • Zhu H; AbbVie Inc., North Chicago, Illinois, USA.
  • Comess KM; AbbVie Inc., North Chicago, Illinois, USA.
  • Shaw B; AbbVie Inc., North Chicago, Illinois, USA.
  • The J; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Lima-Fernandes E; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Szewczyk MM; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Cheng D; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Klinge KL; AbbVie Inc., North Chicago, Illinois, USA.
  • Li HQ; AbbVie Inc., North Chicago, Illinois, USA.
  • Pliushchev M; AbbVie Inc., North Chicago, Illinois, USA.
  • Algire MA; AbbVie Inc., North Chicago, Illinois, USA.
  • Maag D; AbbVie Inc., North Chicago, Illinois, USA.
  • Guo J; AbbVie Inc., North Chicago, Illinois, USA.
  • Dietrich J; AbbVie Inc., North Chicago, Illinois, USA.
  • Panchal SC; AbbVie Inc., North Chicago, Illinois, USA.
  • Petros AM; AbbVie Inc., North Chicago, Illinois, USA.
  • Sweis RF; AbbVie Inc., North Chicago, Illinois, USA.
  • Torrent M; AbbVie Inc., North Chicago, Illinois, USA.
  • Bigelow LJ; AbbVie Inc., North Chicago, Illinois, USA.
  • Senisterra G; AbbVie Inc., North Chicago, Illinois, USA.
  • Li F; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Kennedy S; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Wu Q; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Osterling DJ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Lindley DJ; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Gao W; AbbVie Inc., North Chicago, Illinois, USA.
  • Galasinski S; AbbVie Inc., North Chicago, Illinois, USA.
  • Barsyte-Lovejoy D; AbbVie Inc., North Chicago, Illinois, USA.
  • Vedadi M; AbbVie Inc., North Chicago, Illinois, USA.
  • Buchanan FG; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Chiang GG; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • Sun C; AbbVie Inc., North Chicago, Illinois, USA.
  • Pappano WN; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Nat Chem Biol ; 13(4): 389-395, 2017 04.
Article en En | MEDLINE | ID: mdl-28135237
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Complejo Represivo Polycomb 2 / Indanos / Antineoplásicos Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Complejo Represivo Polycomb 2 / Indanos / Antineoplásicos Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos