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

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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

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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.

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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: Qi, Wei
Zhao, Kehao
Huang, Ying
Zhang, Hailong
Zhang, Man
Zhang, Jeff
Li, Ling
Zhao, Mengxi
Chen, Zijun
Fang, Douglas
Ge, Hui
Lingel, Andreas
Lin, Ying
Liu, Yueqin
Wang, Zhaofu
Yu, Yanyan
Zhang, Qiong
Li, En
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: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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

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An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

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