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

The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.

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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Crossref · 10.1038/nchembio.2306

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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
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
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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