Sijie Wang; Aktan Alpsoy; Surbhi Sood; Sandra Carolina Ordonez-Rubiano; Alisha Dhiman; Yixing Sun; Guanming Jiao; Casey J. Krusemark; Emily Dykhuizen
ChemBioChem, 2021, 22, 2335-2344
https://doi.org/10.1002/cbic.202100118

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 K d 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.