Polycomb Paralog Chromodomain Inhibitors Active against Both CBX6 and CBX8*

ChemMedChem. 2021 Oct 6;16(19):3027-3034. doi: 10.1002/cmdc.202100262. Epub 2021 Jul 23.


Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing either the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 (H3) via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the -2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cell-based studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line.

Keywords: CBX inhibitors; CBX6; CBX8; Methyllysine reader proteins; polycomb paralogs.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Molecular Structure
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors*
  • Polycomb Repressive Complex 1 / metabolism
  • Polycomb-Group Proteins / antagonists & inhibitors*
  • Polycomb-Group Proteins / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • CBX8 protein, human
  • Ligands
  • Peptides
  • Polycomb-Group Proteins
  • cbx6 protein, human
  • Polycomb Repressive Complex 1