Reprogramming CBX8-PRC1 function with a positive allosteric modulator. Issue 4 (21st April 2022) - Suh, Junghyun L.
Summary: 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. Highlights: Structure-based design of selective, high-affinity chemical probe against CBX8 Cellular reporter identifies UNC7040, a PAM of CBX8 PAM activity blocks H3K27me3 binding and enhances CBX8 affinity for nucleic acids UNC7040 evicts PRC1 from H3K27me3 targets triggering DLBCL cell differentiation Abstract : Suh et al. describe the discovery of UNC7040, a potent, cellularly active positive allosteric modulator of CBX8. In addition to blocking H3K27me3 binding, UNC7040 enhances CBX8 interaction with nucleic acids leading to efficient canonical PRC1 eviction and activation of Polycomb target genes.