ArticleNature chemical biology2017
An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.
Article in Nature chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 171 papers.
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Who cites it
171 citing papers in PubMed, 316 citations in OpenAlex.
- Structural characteristics and SARs of EZH2 inhibitors.Molecular diversity · 2026Review
- Article
- Epigenetics in development, disease, and therapy: from mechanisms to clinical interventions.Science China. Life sciences · 2026Review
- Polycomb Repressive Complex 2 (PRC2): A Context-Dependent Epigenetic Regulator of Brain Aging.Biomolecules · 2026Review
- Article
- The role of the WD40-repeat protein family in cancer.Molecular cancer · 2026Review
- Chemical Epigenetics: Small Molecules Targeting Chromatin Modifiers in Disease Modulation.Cell biochemistry and biophysics · 2026Review
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer.Experimental hematology & oncology · 2026Review
- Metronomic 5-Fluorouracil and Vinorelbine Reduce Cancer Stemness and Modulate EZH2/NOTCH-1/STAT3 Signaling in Triple-Negative Breast Cancer Spheroids.International journal of molecular sciences · 2025Article
- Chromatin repression by PRC2 results in reduced gene expression driving key features of CD8 T cell exhaustion.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Therapeutic Targeting of Protein Lysine and Arginine Methyltransferases: Principles and Strategies for Inhibitor Design.International journal of molecular sciences · 2025Review
- Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.bioRxiv : the preprint server for biology · 2025Article
- Inhibition of EED-mediated histone methylation alleviates neuroinflammation by suppressing WNT-mediated dendritic cell migration.Journal of neuroinflammation · 2025Article
- A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.Journal of medicinal chemistry · 2025Article
- Gestational diabetes mellitus causes genome hyper-methylation of oocyte via increased EZH2.Nature communications · 2025Article
- CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells.Scientific reports · 2025Article
- Cancer epigenetic therapy: recent advances, challenges, and emerging opportunities.Epigenomics · 2025Review
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
111 more citing papers are in PubMed but not listed here.
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Authors and funding
40 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.