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While most therapeutic strategies target its catalytic EZH2 subunit, inhibition of its allosteric EED subunit offers a potential strategy for overcoming emerging drug resistance. Here, we identify and characterize AN\u2010329\/11627212, a novel EED\u2010targeting compound, through structure\u2010based virtual screening. Biochemical and biophysical analyses confirm its direct binding to EED. Strikingly, x\u2010ray crystallography reveals that AN\u2010329\/11627212 induces dissociation of the pre\u2010bound EED\u2010H3K27me3 complex, consistent with a \u201chit\u2010and\u2010run\u201d inhibitory mechanism. Detailed molecular docking revealed that AN\u2010329\/11627212 embeds itself within EED's allosteric H3K27me3\u2010binding pocket. Functionally, AN\u2010329\/11627212 exhibited anti\u2010proliferative activity in PRC2\u2010dependent cancer cell lines, most potently against HCT116 colon cancer cells. Our work identifies AN\u2010329\/11627212 as a novel chemotype that acts by dissociating the EED\u2010H3K27me3 complex, providing a foundation for developing next\u2010generation anti\u2010tumor agents targeting PRC2.<\/jats:p>","DOI":"10.1002\/cbdv.71171","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T16:26:09Z","timestamp":1775060769000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual Screening and Characterization of AN\u2010329\/11627212 as a Novel Inhibitor Disrupting the EED\u2010H3K27me3 Interaction"],"prefix":"10.1002","volume":"23","author":[{"given":"Ning","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Phytochemistry and Natural Medicines Kunming Institute of Botany, Chinese Academy of Sciences  Kunming China"},{"name":"University of Chinese Academy of Sciences Beijing 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