ArticleCell chemical biology2019
Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7.
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Article in Cell chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 60 citations in OpenAlex.
- H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.Nature genetics · 2026Article
- Discovery of Small-Molecule Antagonists of PHF1 and 19 Demonstrates the Ligandability of PRC2 Accessory Proteins.ACS bio & med chem Au · 2026Article
- Application of a MALDI mass spectrometry assay to identify covalent fragments targeting the methyl-lysine reader protein MPP8.SLAS discovery : advancing life sciences R & D · 2026Article
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Influence of the Electrostatic Tuning of Alkyl and Benzyl Groups on Cation-π Interactions in Histone Reader Proteins and β-Hairpin Peptides.Biochemistry · 2026Article
- KAT6A chimeras form a self-reinforcing epigenetic module with NURF and MLL/COMPASS to sustain AML.Genome biology · 2025Article
- Structural insights into how DEK nucleosome binding facilitates H3K27 trimethylation in chromatin.Nature structural & molecular biology · 2025Article
- A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma.Molecular cell · 2025Article
- Epigenetic reader chromodomain as a potential therapeutic target.RSC chemical biology · 2025Review
- Unravelling the impact of the chromobox proteins in human cancers.Cell death & disease · 2025Review
- Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer.Clinical epigenetics · 2025Review
- Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells.Blood neoplasia · 2024Article
- Discovery of CHD1 Antagonists for PTEN-Deficient Prostate Cancer.Journal of medicinal chemistry · 2024Article
- How CBX proteins regulate normal and leukemic blood cells.FEBS letters · 2024Review
- Investigating the Cytosolic Delivery of Proteins by Lipid Nanoparticles Using the Chloroalkane Penetration Assay.Biochemistry · 2024Article
- Reader-Effectors as Actuators of Epigenome Editing.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Predicting prime editing efficiency and product purity by deep learning.Nature biotechnology · 2023Article
- Chemical tools targeting readers of lysine methylation.Current opinion in chemical biology · 2023Review
- PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1.Molecular cell · 2023Article
- Chromatin structure and context-dependent sequence features control prime editing efficiency.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
20 authors at 6 institutions in 2 countries.
Kelsey N LambCenter 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.
Daniel BstehInstitute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria; Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Sarah N DishmanCenter 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.
Hagar F MoussaInstitute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
Huitao FanLineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jacob I StuckeyCenter 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.
Jacqueline L NorrisCenter 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.
Stephanie H CholenskyCenter 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.
Dongxu LiLineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jingkui WangResearch Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria.
Cari SagumDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Benjamin Z StantonDivision of Preclinical Innovation, National Center for Advancing Translational Sciences NIH, Rockville, MD 20850, USA.
Mark T BedfordDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Kenneth H PearceCenter 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.
Terry P KenakinDepartment of Pharmacology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Dmitri B KireevCenter 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.
Gang Greg WangLineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lindsey I JamesCenter 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.
Oliver BellInstitute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria; Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. Electronic address: oliver.bell@med.usc.edu.
Stephen V FryeCenter 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; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: svfrye@email.unc.edu.
University of North Carolina at Chapel Hill · USThe University of Texas MD Anderson Cancer Center · USUniversity of Southern California · USInstitute of Molecular Biotechnology · ATNational Center for Advancing Translational Sciences · USResearch Institute of Molecular Pathology · AT
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI David Darr · 1985 to 2026
$201.5MDISCOVERY OF CHEMICAL PROBES FOR METHYL-LYSINE READERSR01GM100919 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI FRYE, STEPHEN VERNON · 2012 to 2019
$2.9MPOLYCOMB REPRESSIVE COMLEXE AS KEY REGULATORS OF HIV LATENCY AND TARGETS FOR LATENCY REVERSALR61DA047023 · NIDA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JAMES, LINDSEY INGERMAN · 2018 to 2020
$2.7MCancer Epigenetics: A novel PRC2 Dysregulation Mechanism in Multiple MyelomaR01CA211336 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WANG, G GREG · 2017 to 2021
$2.0MDetermining the Role of DNA Methylation Deregulation in OncogenesisR01CA215284 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WANG, G GREG · 2017 to 2021
$1.7MDISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINSR01CA218392 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI FRYE, STEPHEN VERNON · 2018 to 2020
$1.5MNCI NIH HHS P30 CA016086NCI NIH HHS R01 CA211336NCI NIH HHS R01 CA215284NCI NIH HHS R01 CA218392NIDA NIH HHS R61 DA047023NIGMS NIH HHS R01 GM100919
Abstract
Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM) peptidomimetic, UNC4976, of nucleic acid binding by CBX7, a chromodomain methyl-lysine reader of Polycomb repressive complex 1. The PAM activity of UNC4976 resulted in enhanced efficacy across three orthogonal cellular assays by simultaneously antagonizing H3K27me3-specific recruitment of CBX7 to target genes while increasing non-specific binding to DNA and RNA. PAM activity thereby reequilibrates PRC1 away from H3K27me3 target regions. Together, our discovery and characterization of UNC4976 not only revealed the most cellularly potent PRC1-specific chemical probe to date, but also uncovers a potential mechanism of Polycomb regulation with implications for non-histone lysine methylated interaction partners.
Indexed as
Drug DiscoveryAllosteric RegulationAnimalsHEK293 CellsHeLa CellsHumansMicePeptidomimeticsPolycomb Repressive Complex 1CBX7 protein, humanPeptidomimeticsPolycomb Repressive Complex 1allosterismchromatinchromodomainmethyl-lysine readerpolycombpositive allosteric modulator
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