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:
- more »
- 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.
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.
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.
@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}
}
Works referenced in this record:
The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression
journal, April 2013
- Chan, K. -M.; Fang, D.; Gan, H.
- Genes & Development, Vol. 27, Issue 9
Selective inhibition of BET bromodomains
journal, September 2010
- Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah
- Nature, Vol. 468, Issue 7327
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997
- Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance
journal, April 2016
- Brooun, Alexei; Gajiwala, Ketan S.; Deng, Ya-Li
- Nature Communications, Vol. 7, Issue 1
A gene complex controlling segmentation in Drosophila
journal, December 1978
- Lewis, E. B.
- Nature, Vol. 276, Issue 5688
Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2
journal, April 2013
- Knutson, S. K.; Warholic, N. M.; Wigle, T. J.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 19
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions
journal, November 2004
- Krissinel, E.; Henrick, K.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
journal, September 2002
- Cao, R.; Wang, L.; Wang, H.
- Science, Vol. 298, Issue 5595
Ezh1 and Ezh2 Maintain Repressive Chromatin through Different Mechanisms
journal, November 2008
- Margueron, Raphael; Li, Guohong; Sarma, Kavitha
- Molecular Cell, Vol. 32, Issue 4
Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery
journal, September 2004
- Lo, Mei-Chu; Aulabaugh, Ann; Jin, Guixian
- Analytical Biochemistry, Vol. 332, Issue 1
Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma
journal, March 2013
- Lewis, P. W.; Muller, M. M.; Koletsky, M. S.
- Science, Vol. 340, Issue 6134
Role of the polycomb protein EED in the propagation of repressive histone marks
journal, September 2009
- Margueron, Raphael; Justin, Neil; Ohno, Katsuhito
- Nature, Vol. 461, Issue 7265
Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2
journal, October 2015
- Jiao, L.; Liu, X.
- Science, Vol. 350, Issue 6258
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
journal, October 2012
- McCabe, Michael T.; Ott, Heidi M.; Ganji, Gopinath
- Nature, Vol. 492, Issue 7427
A model for transmission of the H3K27me3 epigenetic mark
journal, October 2008
- Hansen, Klaus H.; Bracken, Adrian P.; Pasini, Diego
- Nature Cell Biology, Vol. 10, Issue 11
An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1
journal, April 2013
- Konze, Kyle D.; Ma, Anqi; Li, Fengling
- ACS Chemical Biology, Vol. 8, Issue 6
Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
journal, July 2011
- Morin, Ryan D.; Mendez-Lago, Maria; Mungall, Andrew J.
- Nature, Vol. 476, Issue 7360
Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas
journal, November 2010
- Sneeringer, C. J.; Scott, M. P.; Kuntz, K. W.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 49
Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)
journal, February 2012
- McCabe, M. T.; Graves, A. P.; Ganji, G.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 8
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors
journal, April 2015
- Gibaja, V.; Shen, F.; Harari, J.
- Oncogene, Vol. 35, Issue 5
The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
journal, September 2007
- Niesen, Frank H.; Berglund, Helena; Vedadi, Masoud
- Nature Protocols, Vol. 2, Issue 9
Data processing and analysis with the autoPROC toolbox
journal, March 2011
- Vonrhein, Clemens; Flensburg, Claus; Keller, Peter
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
journal, January 2010
- Morin, Ryan D.; Johnson, Nathalie A.; Severson, Tesa M.
- Nature Genetics, Vol. 42, Issue 2
Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2
journal, April 2016
- Justin, Neil; Zhang, Ying; Tarricone, Cataldo
- Nature Communications, Vol. 7, Issue 1
Epigenetic protein families: a new frontier for drug discovery
journal, April 2012
- Arrowsmith, Cheryl H.; Bountra, Chas; Fish, Paul V.
- Nature Reviews Drug Discovery, Vol. 11, Issue 5
The Polycomb complex PRC2 and its mark in life
journal, January 2011
- Margueron, Raphaël; Reinberg, Danny
- Nature, Vol. 469, Issue 7330
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4