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

doi:10.1038/nchembio.2306

Title: The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex

Full Record
Other Related Research

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:

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. more »

Publication Date:: Mon Jan 30 00:00:00 EST 2017

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: INDUSTRY

OSTI Identifier:: 1351368

Resource Type:: Journal Article

Resource Relation:: Journal Name: Nature Chemical Biology; Journal Volume: 13; Journal Issue: 4

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.

Copy to clipboard


                    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.

Copy to clipboard


                    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.

Copy to clipboard


                    
@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},

  number       = 4,

  volume       = 13,

  place        = {United States},

  year         = {Mon Jan 30 00:00:00 EST 2017},

  month        = {Mon Jan 30 00:00:00 EST 2017}

}

Copy to clipboard

Journal Article:

DOI: 10.1038/nchembio.2306

Other availability

Find in Google Scholar

Search WorldCat to find libraries that may hold this journal

Save / Share:

Export Metadata

Save to My Library

Similar records in OSTI.GOV collections:

SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Journal Article Curtin, Michael L. ; Pliushchev, Marina A. ; Li, Huan-Qiu ; ... - Bioorganic and Medicinal Chemistry Letters
DOI: 10.1016/j.bmcl.2017.02.030
Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

Journal Article Lingel, Andreas ; Sendzik, Martin ; Huang, Ying ; ... - Journal of Medicinal Chemistry

PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful propertymore »« less
DOI: 10.1021/acs.jmedchem.6b01473
Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2

Journal Article Barnash, Kimberly D. ; The, Juliana ; Norris-Drouin, Jacqueline L. ; ... - ACS Combinatorial Science

The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein–protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED’s recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide tomore »« less
DOI: 10.1021/acscombsci.6b00174
Polycomb-like proteins link the PRC2 complex to CpG islands

Journal Article Li, Haojie ; Liefke, Robert ; Jiang, Junyi ; ... - Nature (London)

The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and has essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like (PCL) proteins, such as PHF1, MTF2 and PHF19, are PRC2-associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate the enzymatic activity of PRC2 or the recruitment of PRC2 to specific genomic loci4,5,6,7,8,9,10,11,12,13. Mammalian PRC2-binding sites are enriched in CG content, which correlates with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood.more »« less
DOI: 10.1038/nature23881
Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor

Journal Article Zhao, Jing ; Du, Yuhong ; Horton, John R. ; ... - Proc. Natl. Acad. Sci. USA

The 14-3-3 family of phosphoserine/threonine-recognition proteins engage multiple nodes in signaling networks that control diverse physiological and pathophysiological functions and have emerged as promising therapeutic targets for such diseases as cancer and neurodegenerative disorders. Thus, small molecule modulators of 14-3-3 are much needed agents for chemical biology investigations and therapeutic development. To analyze 14-3-3 function and modulate its activity, we conducted a chemical screen and identified 4-[(2Z)-2-[4-formyl-6-methyl-5-oxo-3-(phosphonatooxymethyl)pyridin-2-ylidene]hydrazinyl]benzoate as a 14-3-3 inhibitor, which we termed FOBISIN (FOurteen-three-three BInding Small molecule INhibitor) 101. FOBISIN101 effectively blocked the binding of 14-3-3 with Raf-1 and proline-rich AKT substrate, 40 kD{sub a} and neutralized themore »« less
DOI: 10.1073/pnas.1100012108

Similar Records