UNC7040 (UNC-7040) is a potent, specific positive allosteric modulator of CBX8 with EC50 of 0.84 uM in CBX8 reporter assays.
UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids.
UNC7040 binds to CBX8 chromodomain with KD of 0.16 uM in SPAR assays, did not display binding to CBX1, CBX3, or CBX5, which are CBX CDs of human heterochromatin protein 1 paralogs.
UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines.
UNC7040 efficiently impairs PRC1 targeting and transcriptional repression by disrupting CBX8 interaction with H3K27me3.
The PAM activity of UNC7040 increases CBX8's affinity for nucleic acids and enhances cellular efficacy to provide a powerful tool to dissect its canonical and non-canonical roles in gene regulation.
