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Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity. Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.


Junghyun L Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M Rectenwald, Jacqueline L Norris, Stephanie H Cholensky, Cari Sagum, Jessica D Umana, Dongxu Li, Brian Hardy, Mark T Bedford, Shannon M Mumenthaler, Heinz-Josef Lenz, Yong-Mi Kim, Gang Greg Wang, Ken H Pearce, Lindsey I James, Dmitri B Kireev, Catherine A Musselman, Stephen V Frye, Oliver Bell. Reprogramming CBX8-PRC1 function with a positive allosteric modulator. Cell chemical biology. 2022 Apr 21;29(4):555-571.e11

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PMID: 34715055

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