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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.

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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1351368
Resource Type:
Journal Article
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 13; Journal Issue: 4; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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, and Pappano, William N. The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex. United States: N. p., 2017. Web. doi:10.1038/nchembio.2306.
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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. The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex. United States. doi:10.1038/nchembio.2306.
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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, and Pappano, William N. Mon . "The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex". United States. doi:10.1038/nchembio.2306.
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@article{osti_1351368,
title = {The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex},
author = {He, Yupeng and Selvaraju, Sujatha and Curtin, Michael L. and Jakob, Clarissa G. and Zhu, Haizhong and Comess, Kenneth M. and Shaw, Bailin and The, Juliana and Lima-Fernandes, Evelyne and Szewczyk, Magdalena M. and Cheng, Dong and Klinge, Kelly L. and Li, Huan-Qiu and Pliushchev, Marina and Algire, Mikkel A. and Maag, David and Guo, Jun and Dietrich, Justin and Panchal, Sanjay C. and Petros, Andrew M. and Sweis, Ramzi F. and Torrent, Maricel and Bigelow, Lance J. and Senisterra, Guillermo and Li, Fengling and Kennedy, Steven and Wu, Qin and Osterling, Donald J. and Lindley, David J. and Gao, Wenqing and Galasinski, Scott and Barsyte-Lovejoy, Dalia and Vedadi, Masoud and Buchanan, Fritz G. and Arrowsmith, Cheryl H. and Chiang, Gary G. and Sun, Chaohong and Pappano, William N.},
abstractNote = {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.},
doi = {10.1038/nchembio.2306},
journal = {Nature Chemical Biology},
issn = {1552-4450},
number = 4,
volume = 13,
place = {United States},
year = {2017},
month = {1}
}
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DOI:  10.1038/nchembio.2306
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