The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

Autor: 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.; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Szewczyk MM; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Cheng D; AbbVie Inc., North Chicago, Illinois, USA., 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; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., 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.; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Osterling DJ; AbbVie Inc., North Chicago, Illinois, USA., Lindley DJ; AbbVie Inc., North Chicago, Illinois, USA., Gao W; AbbVie Inc., North Chicago, Illinois, USA., Galasinski S; AbbVie Inc., North Chicago, Illinois, USA., Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Vedadi M; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada., Buchanan FG; AbbVie Inc., North Chicago, Illinois, USA., Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Chiang GG; AbbVie Inc., North Chicago, Illinois, USA.; eFFECTOR Therapeutics, San Diego, California, USA., Sun C; AbbVie Inc., North Chicago, Illinois, USA., Pappano WN; AbbVie Inc., North Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2017 Apr; Vol. 13 (4), pp. 389-395. Date of Electronic Publication: 2017 Jan 30.
DOI: 10.1038/nchembio.2306
Abstrakt: 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.
Databáze: MEDLINE
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