# DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $520,558

## Abstract

Chromatin is the complex of histone proteins, RNA, and DNA that efficiently packages the genome within
each human cell. The regulation of chromatin accessibility via post-translational modifications (PTM) of histones
is of great current interest as opportunities for pharmacological intervention in the ‘writing’, ‘reading’ and ‘erasing’
of these PTMs are significant. The biological consequences of most PTMs result from their recruitment of
regulatory machinery via protein-protein interactions directly facilitated by the PTM. The binding domains
involved in PTM recognition on chromatin are referred to as “readers”.
 The overarching objective of this program is to develop an in vivo chemical probe of the CBX reader
domains of Polycomb repressive complex 1 (PRC1). There are eight human CBX chromodomains that function
as methyl-lysine (Kme) recognition domains (readers) within the two major chromatin repressive complexes that
are conserved across higher eukaryotes. CBX proteins 1, 3 and 5 are associated with the heterochromatin
protein 1 (HP1) complex. Their Kme binding activity is required for compaction and repression of chromatin that
bears the histone H3, lysine 9 trimethyl (H3K9me3) mark. CBX proteins 2, 4, 6, 7, and 8 are associated with the
PRC1 which binds the H3K27me3 mark. As appropriate repression of genomic loci is critical throughout
organismal development and differentiation, dysregulation of HP1 and Polycomb pathways is implicated in many
disease states and an in vivo chemical probe targeting PRC1 would be a first-in-class agent targeting a pathway
of high disease relevance and would also represent a unique tool to explore Polycomb biology in complex in vivo
systems.
 The deliverable from this effort will be a high-quality in vivo chemical probe, freely available to the
academic community, with confirmed activity and well characterized mechanism versus the CBX readers of
PRC1 to catalyze progression of this target toward new therapeutic discoveries in oncology and, potentially,
other diseases.

## Key facts

- **NIH application ID:** 9907857
- **Project number:** 5R01CA218392-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Stephen Vernon Frye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,558
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907857

## Citation

> US National Institutes of Health, RePORTER application 9907857, DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS (5R01CA218392-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9907857. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*