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Nat Chem Biol. 2017 Apr;13(4):389-395. doi: 10.1038/nchembio.2306. Epub 2017 Jan 30.

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

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AbbVie Inc., North Chicago, Illinois, USA.
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
eFFECTOR Therapeutics, San Diego, California, USA.


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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