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Discovery and Characterization of a Cellularly Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7

104 Pages Posted: 2 May 2019 Sneak Peek Status: Published

See all articles by Kelsey N. Lamb

Kelsey N. Lamb

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Daniel Bsteh

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology; University of Southern California, Keck School of Medicine, Department of Biochemistry and Molecular Medicine; University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center

Sarah N. Dishman

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Hagar F. Moussa

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology

Huitao Fan

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center; University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Jacob I. Stuckey

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Jacqueline L. Norris

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Stephanie H. Cholensky

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Dongxu Li

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center; University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Jingkui Wang

Vienna Biocenter, Research Institute of Molecular Pathology

Cari Sagum

University of Texas at Houston, MD Anderson Cancer Center, Department of Epigenetics and Molecular Carcinogenesis

Benjamin Z. Stanton

National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation; Stanford University, School of Medicine, Department of Pathology; Stanford University, School of Medicine, Department of Developmental Biology; National Institutes of Health (NIH), National Heart, Lung and Blood Institute, Systems Biology Center, Laboratory of Epigenome Biology

Mark T. Bedford

University of Texas at Houston, Health Science Center at Houston (UTHealth), MD Anderson Cancer Center, Department of Epigenetics and Molecular Carcinogenesis

Terry P. Kenakin

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Pharmacology

Dmitri B. Kireev

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Gang Greg Wang

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center; University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Lindsey I. James

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Oliver Bell

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology; University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center; University of Southern California, Keck School of Medicine, Department of Biochemistry and Molecular Medicine

Stephen Frye

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

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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), 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.

Suggested Citation

Lamb, Kelsey N. and Bsteh, Daniel and Dishman, Sarah N. and Moussa, Hagar F. and Fan, Huitao and Stuckey, Jacob I. and Norris, Jacqueline L. and Cholensky, Stephanie H. and Li, Dongxu and Wang, Jingkui and Sagum, Cari and Stanton, Benjamin Z. and Bedford, Mark T. and Kenakin, Terry P. and Kireev, Dmitri B. and Wang, Gang Greg and James, Lindsey I. and Bell, Oliver and Frye, Stephen, Discovery and Characterization of a Cellularly Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7 (April 25, 2019). Available at SSRN: https://ssrn.com/abstract=3378003 or http://dx.doi.org/10.2139/ssrn.3378003
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kelsey N. Lamb

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Daniel Bsteh

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology

Vienna
Austria

University of Southern California, Keck School of Medicine, Department of Biochemistry and Molecular Medicine

Los Angeles, CA
United States

University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center

1441 Eastlake Ave
Los Angeles, CA 90089
United States

Sarah N. Dishman

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Hagar F. Moussa

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology

Vienna
Austria

Huitao Fan

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center

102 Ridge Road
Chapel Hill, NC 27514
United States

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Chapel Hill, NC 27514
United States

Jacob I. Stuckey

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Jacqueline L. Norris

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Stephanie H. Cholensky

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Dongxu Li

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center

102 Ridge Road
Chapel Hill, NC 27514
United States

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Chapel Hill, NC 27514
United States

Jingkui Wang

Vienna Biocenter, Research Institute of Molecular Pathology

Vienna
Austria

Cari Sagum

University of Texas at Houston, MD Anderson Cancer Center, Department of Epigenetics and Molecular Carcinogenesis

Smithville, TX
United States

Benjamin Z. Stanton

National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation ( email )

Rockville, MD
United States

Stanford University, School of Medicine, Department of Pathology ( email )

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Stanford University, School of Medicine, Department of Developmental Biology ( email )

Stanford, CA 94305
United States

National Institutes of Health (NIH), National Heart, Lung and Blood Institute, Systems Biology Center, Laboratory of Epigenome Biology ( email )

Bethesda, MD
United States

Mark T. Bedford

University of Texas at Houston, Health Science Center at Houston (UTHealth), MD Anderson Cancer Center, Department of Epigenetics and Molecular Carcinogenesis

Smithville, TX
United States

Terry P. Kenakin

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Pharmacology

Chapel Hill, NC
United States

Dmitri B. Kireev

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Gang Greg Wang

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Lineberger Comprehensive Cancer Center

102 Ridge Road
Chapel Hill, NC 27514
United States

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Biochemistry and Biophysics

Chapel Hill, NC 27514
United States

Lindsey I. James

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Oliver Bell

Vienna Biocenter, Austrian Academy of Sciences, Institute of Molecular Biotechnology ( email )

Vienna
Austria

University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center ( email )

1441 Eastlake Ave
Los Angeles, CA 90089
United States

University of Southern California, Keck School of Medicine, Department of Biochemistry and Molecular Medicine ( email )

Los Angeles, CA
United States

Stephen Frye (Contact Author)

University of North Carolina (UNC) at Chapel Hill, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery ( email )

102 Ridge Road
Chapel Hill, NC 27514
United States

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