A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation

Chembiochem. 2021 Jul 1;22(13):2335-2344. doi: 10.1002/cbic.202100118. Epub 2021 May 28.


Polycomb group (PcG) proteins are epigenetic regulators that facilitate both embryonic development and cancer progression. PcG proteins form Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). PRC2 trimethylates histone H3 lysine 27 (H3K27me3), a histone mark recognized by the N-terminal chromodomain (ChD) of the CBX subunit of canonical PRC1. There are five PcG CBX paralogs in humans. CBX2 in particular is upregulated in a variety of cancers, particularly in advanced prostate cancers. Using CBX2 inhibitors to understand and target CBX2 in prostate cancer is highly desirable; however, high structural similarity among the CBX ChDs has been challenging for developing selective CBX ChD inhibitors. Here, we utilize selections of focused DNA encoded libraries (DELs) for the discovery of a selective CBX2 chromodomain probe, SW2_152F. SW2_152F binds to CBX2 ChD with a Kd of 80 nM and displays 24-1000-fold selectivity for CBX2 ChD over other CBX paralogs in vitro. SW2_152F is cell permeable, selectively inhibits CBX2 chromatin binding in cells, and blocks neuroendocrine differentiation of prostate cancer cell lines in response to androgen deprivation.

Keywords: CBX2; Chromodomain Inhibitor; DNA-Encoded Library; Neuroendocrine Differentiation; Prostate Cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Androgen Antagonists / metabolism
  • Carcinoma, Neuroendocrine / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Gene Expression Regulation, Neoplastic / genetics*
  • Histones / metabolism
  • Humans
  • Ligands
  • Male
  • Polycomb Repressive Complex 1 / chemistry*
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb-Group Proteins / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism


  • Androgen Antagonists
  • CBX2 protein, human
  • Histones
  • Ligands
  • Polycomb-Group Proteins
  • Small Molecule Libraries
  • Polycomb Repressive Complex 1