ArticleScientific reports2019
Discovery of selective activators of PRC2 mutant EED-I363M.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.bioRxiv : the preprint server for biology · 2025Article
- Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics.Drug discovery today · 2024Review
- The Intersection of Epigenetic Alterations and Developmental State in Pediatric Ependymomas.Developmental neuroscience · 2024Review
- Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer.International journal of molecular sciences · 2022Review
- Mechanisms of Polycomb group protein function in cancer.Cell research · 2022Review
- Discovering new biology with drug-resistance alleles.Nature chemical biology · 2021Review
- Improved methods for targeting epigenetic reader domains of acetylated and methylated lysine.Current opinion in chemical biology · 2021Review
- Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).Journal of medicinal chemistry · 2021Article
- Polycomb Gene Silencing Mechanisms: PRC2 Chromatin Targeting, H3K27me3 'Readout', and Phase Separation-Based Compaction.Trends in genetics : TIG · 2021Review
- Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7.Cell chemical biology · 2019Article
- Targeting non-bromodomain chromatin readers.Nature structural & molecular biology · 2019Review
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. Polycomb repressive complex 2 (PRC2), which contains core subunits (EZH2, EED, and SUZ12), regulates gene activity by trimethylation of histone 3 lysine 27. The dysregulation of PRC2 catalytic activity by mutations has been implicated in cancer and other diseases. Among the mutations that cause PRC2 malfunction, an I363M LOF mutation of EED has been identified in myeloid disorders, where it prevents allosteric activation of EZH2 catalysis. We describe structure-based design and computational simulations of ligands created to ameliorate this LOF. Notably, these compounds selectively stimulate the catalytic activity of PRC2-EED-I363M over wildtype-PRC2. Overall, this work demonstrates the feasibility of developing targeted therapeutics for PRC2-EED-I363M that act as allosteric agonists, potentially correcting this LOF mutant phenotype.
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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.