ArticleCell chemical biology2022
Reprogramming CBX8-PRC1 function with a positive allosteric modulator.
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Article in Cell chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
1.2field-weighted citation impact, top 21% of its field
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Who cites it
20 citing papers in PubMed, 23 citations in OpenAlex.
- Article
- Embryonic stem cell factors DPPA2/4 amplify active H3K4me3-H2AK119ub chromatin domains in non-small cell lung cancer.Genes & development · 2026Article
- Discovery of Small-Molecule Antagonists of PHF1 and 19 Demonstrates the Ligandability of PRC2 Accessory Proteins.ACS bio & med chem Au · 2026Article
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Mono-ubiquitination of histone H2A lysine 119 (H2AK119Ub): its multifaceted role in biology and implication in diseases.MedScience · 2026Review
- 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
- Dynamic PRC1-CBX8 stabilizes a porous structure of chromatin condensates.Nature structural & molecular biology · 2025Article
- 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
- 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
- Chromobox proteins in cancer: Multifaceted functions and strategies for modulation (Review).International journal of oncology · 2023Review
- Review
- Article
- Discovery of Potent Peptidomimetic Antagonists for Heterochromatin Protein 1 Family Proteins.ACS omega · 2022Article
- Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.Frontiers in cell and developmental biology · 2022Review
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Authors and funding
27 authors at 5 institutions in 2 countries.
Junghyun L SuhCenter 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 BstehDepartment of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Bryce HartCenter 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.
Yibo SiDepartment of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Tyler M WeaverUniversity of Iowa, Department of Biochemistry, Iowa City, IA 52242, USA.
Carina PribitzerInstitute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
Roy LauLawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Shivani SoniDivision of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Heather OganaDepartment of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA.
Justin M RectenwaldCenter 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.
Cari SagumDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Jessica D UmanaCenter 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.
Brian HardyCenter 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.
Mark T BedfordDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Shannon M MumenthalerLawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Heinz-Josef LenzDivision of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Yong-Mi KimDepartment of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, 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.
Ken 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.
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; Lineberger Comprehensive Cancer Center, 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.
Catherine A MusselmanUniversity of Iowa, Department of Biochemistry, Iowa City, IA 52242, USA; University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics, Aurora, CO 80045, USA.
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.
Oliver BellDepartment of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria. Electronic address: oliver.bell@med.usc.edu.
University of North Carolina at Chapel Hill · USUniversity of Southern California · USThe University of Texas MD Anderson Cancer Center · USUniversity of Iowa · USInstitute of Molecular Biotechnology · AT
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5MUSC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORTP30CA014089 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Fumito Ito · 1985 to 2026
$181.4MViral VectorP30CA086862 · NCI · UNIVERSITY OF IOWA · PI Douglas Robert Spitz · 2000 to 2026
$70.0MMolecular mechanisms of histone signaling in a chromatin relevant contextR35GM128705 · NIGMS · UNIVERSITY OF IOWA · PI Catherine Anne Musselman · 2018 to 2026
$3.8MUnderstanding the niche of minimal residual disease leukemia cellsR01CA172896 · NCI · CHILDREN'S HOSPITAL OF LOS ANGELES · PI KIM, YONG-MI · 2013 to 2022
$3.7MDISCOVERY 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
$2.7MDISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINSR01CA218392 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI FRYE, STEPHEN VERNON · 2018 to 2020
$1.5MComputational and experimental insights into the structure and dynamics of heterochromatinR01GM132299 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI HATHAWAY, NATHANIEL A., KIREEV, DMITRI · 2020 to 2023
$1.2MNCI NIH HHS P30 CA014089NCI NIH HHS P30 CA016086NCI NIH HHS P30 CA086862NCI NIH HHS R01 CA172896NCI NIH HHS R01 CA218392NIDA NIH HHS R61 DA047023NIGMS NIH HHS R01 GM100919NIGMS NIH HHS R01 GM132299NIGMS NIH HHS R35 GM128705
Abstract
Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.
Indexed as
NeoplasmsPolycomb Repressive Complex 1Cell Cycle ProteinsChromatinHistonesHumansPolycomb-Group ProteinsProtein BindingCBX8 protein, humanCell Cycle ProteinsChromatinHistonesPolycomb-Group ProteinsPolycomb Repressive Complex 1PRC1 protein, humanallosterismchemical probeschromatinchromodomainepigeneticsmethyl-lysine readerPolycombpositive allosteric modulator
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