CoChat
Sign Up
Cited by 336Epigenetics and DNA MethylationCancer-related gene regulationChromatin Remodeling and Cancer

The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.

An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

Qi, Wei, Zhao, Kehao, Gu, Justin, Huang, Ying, Wang, Youzhen, Zhang, Hailong, Zhang, Man, Zhang, Jeff, Yu, Zhengtian, Li, Ling, Teng, Lin, Chuai, Shannon, Zhang, Chao, Zhao, Mengxi, Chan, HoMan, Chen, Zijun, Fang, Douglas, Fei, Qi, Feng, Leying, Feng, Lijian, Gao, Yuan, Ge, Hui, Ge, Xinjian, Li, Guobin, Lingel, Andreas, Lin, Ying, Liu, Yueqin, Luo, Fangjun, Shi, Minlong, Wang, Long, Wang, Zhaofu, Yu, Yanyan, Zeng, Jue, Zeng, Chenhui, Zhang, Lijun, Zhang, Qiong, Zhou, Shaolian, Oyang, Counde, Atadja, Peter, Li, En·2017·Nature Chemical Biology
DOI 10.1038/nchembio.2304
Open this paper in CoChat — free account

Abstract

Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.

Overview

Integrity signals

Registry

Crossref · 10.1038/nchembio.2304

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 54 references

Cited by

Sorted by citations

Items 301–336 of 336

Related

See all

Metadata

Authors
Qi, W., Zhao, K., Gu, J., Huang, Y., Wang, Y., Zhang, H., Zhang, M., Zhang, J., Yu, Z., Li, L., Teng, L., Chuai, S., Zhang, C., Zhao, M., Chan, H., Chen, Z., Fang, D., Fei, Q., Feng, L., Feng, L., Gao, Y., Ge, H., Ge, X., Li, G., Lingel, A., Lin, Y., Liu, Y., Luo, F., Shi, M., Wang, L., Wang, Z., Yu, Y., Zeng, J., Zeng, C., Zhang, L., Zhang, Q., Zhou, S., Oyang, C., Atadja, P., & Li, E.
Affiliations
Novartis Institutes for BioMedical Research (CH)
Corresponding author
Li, En
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2017-01-30
Volume
13
Issue
4
Pages
381-388
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.2304
OpenAlex
W2582081516
Cited by
316
References
54
Citations by year
2026: 18 · 2025: 21 · 2024: 39 · 2023: 27 · 2022: 42 · 2021: 33 · 2020: 37 · 2019: 40 · 2018: 32 · 2017: 26
FWCI
15.64
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
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 › Chromatin Remodeling and Cancer
Keywords
polycomb repressive complex 2, EED, H3K27me3, allosteric inhibition, EZH2, histone methyltransferase, small molecule inhibitors, lymphoma, transcriptional regulation, conformational change
MeSH terms
Allosteric Regulation, Animals, Antineoplastic Agents, Binding Sites, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Histones, Humans, Lysine, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Neoplasms, Experimental, Structure-Activity Relationship, Sulfones, Triazoles, Tumor Cells, Cultured, Molecular Structure, Cell Line, Tumor, Cell Proliferation, Mice, Polycomb Repressive Complex 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review