A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation.
Chembiochem
; 22(13): 2335-2344, 2021 07 01.
Article
in En
| MEDLINE
| ID: mdl-33950564
ABSTRACT
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 80â
nM and displays 24-1000-fold selectivity for CBX2 ChD over other CBX paralogs inâ
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Gene Expression Regulation, Neoplastic
/
Carcinoma, Neuroendocrine
/
Small Molecule Libraries
/
Polycomb-Group Proteins
/
Polycomb Repressive Complex 1
Limits:
Humans
/
Male
Language:
En
Journal:
Chembiochem
Year:
2021
Document type:
Article