Cited by 241Epigenetics and DNA MethylationCancer-related gene regulationGenomics and Chromatin Dynamics

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

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·2017·Nature Chemical Biology

DOI 10.1038/nchembio.2306

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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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Authors: He, Y., Selvaraju, S., Curtin, M. L., Jakob, C. G., Zhu, H., Comess, K. M., Shaw, B., The, J., Lima-Fernandes, E., Szewczyk, M. M., Cheng, D., Klinge, K. L., Li, H.-Q., Pliushchev, M., Algire, M. A., Maag, D., Guo, J., Dietrich, J., Panchal, S. C., Petros, A. M., Sweis, R. F., Torrent, M., Bigelow, L. J., Senisterra, G., Li, F., Kennedy, S., Wu, Q., Osterling, D. J., Lindley, D. J., Gao, W., Galasinski, S., Barsyte-Lovejoy, D., Vedadi, M., Buchanan, F. G., Arrowsmith, C. H., Chiang, G. G., Sun, C., & Pappano, W. N.
Affiliations: AbbVie (United States) (US)
University of Toronto (CA)
Corresponding author: Sun, Chaohong
Pappano, William N
ORCID: He, Yupeng
Comess, Kenneth M
Szewczyk, Magdalena M
Cheng, Dong
Guo, Jun
Dietrich, Justin
Panchal, Sanjay C
Petros, Andrew M
Li, Fengling
Wu, Qin
Gao, Wenqing
Vedadi, Masoud
Buchanan, Fritz G
Arrowsmith, Cheryl H
Chiang, Gary G
Sun, Chaohong
Pappano, William N
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2017-01-30
Volume: 13
Issue: 4
Pages: 389-395
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.2306
OpenAlex: W2581052617
Cited by: 224
References: 57
Citations by year: 2026: 9 · 2025: 9 · 2024: 23 · 2023: 19 · 2022: 27 · 2021: 31 · 2020: 23 · 2019: 30 · 2018: 28 · 2017: 23
FWCI: 12.22
Type: journal article
Language: en
Update notices: erratum (2017-08-01)
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
Canadian Institutes of Health Research
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: polycomb repressive complex 2, H3K27me3, protein-protein interaction inhibitors, allosteric inhibition, histone methyltransferase, chemical probes, gene silencing, epigenetic regulation, drug resistance
MeSH terms: Antineoplastic Agents, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indans, Models, Molecular, Protein Binding, Structure-Activity Relationship, Sulfonamides, Tumor Cells, Cultured, Molecular Structure, Cell Line, Tumor, Cell Proliferation, Polycomb Repressive Complex 2

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

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