Reprogramming CBX8-PRC1 function with a positive allosteric modulator

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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
07:16

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

Published on: August 16, 2018

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Junghyun L Suh1, Daniel Bsteh2, Bryce Hart1

  • 1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Cell Chemical Biology
|October 29, 2021
PubMed

Insights

Researchers discovered UNC7040, a potent chemical probe targeting CBX8. This probe selectively removes Polycomb repressive complex 1 (PRC1) from chromatin, inhibiting cancer cell proliferation.

Area of Science:

  • Epigenetics and Gene Regulation
  • Chemical Biology
  • Cancer Research

Background:

  • Polycomb repressive complex 1 (PRC1) is crucial for silencing developmental genes via chromobox (CBX) proteins.
  • Dysregulation of CBX proteins, particularly CBX8, is linked to cancer development.
  • CBX proteins are attractive targets for developing small-molecule chemical probes.

Purpose of the Study:

  • To discover and characterize a potent chemical probe targeting CBX8.
  • To investigate the mechanism of action and cellular effects of the identified probe.

Main Methods:

  • Utilized a quantitative, target-specific cellular assay to screen for modulators of CBX8.
  • Characterized the identified compound's effects on H3K27me3 binding, nucleic acid interactions, and PRC1 chromatin eviction.
  • Assessed the impact of the compound on cancer cell proliferation.

Main Results:

  • Discovered UNC7040, a potent positive allosteric modulator (PAM) of CBX8.
  • UNC7040 antagonizes H3K27me3 binding and enhances nucleic acid interactions of CBX8.
  • UNC7040 treatment leads to selective eviction of CBX8-PRC1 from chromatin, loss of gene silencing, and reduced proliferation in cancer cell lines.

Conclusions:

  • UNC7040 is the most potent CBX8-specific chemical probe identified to date.
  • The findings support a mechanism of Polycomb regulation involving non-specific CBX nucleotide binding.
  • This probe offers a valuable tool for studying Polycomb group proteins and their role in cancer.
Keywords:
Polycomballosterismchemical probeschromatinchromodomainepigeneticsmethyl-lysine readerpositive allosteric modulator

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