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    Discovery of CHD1 Antagonists for PTEN-Deficient Prostate Cancer
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    • Rebecca L. Johnson
      Rebecca L. Johnson
      Center 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, North Carolina 27599, United States
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    • Amanda L. Graboski
      Amanda L. Graboski
      Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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    • Fengling Li
      Fengling Li
      Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
      More by Fengling Li
    • Jacqueline L. Norris-Drouin
      Jacqueline L. Norris-Drouin
      Center 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, North Carolina 27599, United States
      More by Jacqueline L. Norris-Drouin
    • William G. Walton
      William G. Walton
      Departments of Chemistry, Biochemistry & Biophysics, and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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    • Cheryl H. Arrowsmith
      Cheryl H. Arrowsmith
      Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
      Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
      Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
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      Orcidhttps://orcid.org/0000-0002-4971-3250
    • Matthew R. Redinbo
      Matthew R. Redinbo
      Departments of Chemistry, Biochemistry & Biophysics, and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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    • Stephen V. Frye
      Stephen V. Frye
      Center 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, North Carolina 27599, United States
      Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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      Orcidhttps://orcid.org/0000-0002-2415-2215
    • Lindsey I. James*
      Lindsey I. James
      Center 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, North Carolina 27599, United States
      Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-6034-7116
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 22, 20056–20075
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    https://doi.org/10.1021/acs.jmedchem.4c01172
    Published November 7, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    CHD1 is a chromodomain-helicase DNA-binding protein that preferentially recognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3). Genetic studies have established CHD1 as a synthetic lethal target in phosphatase and tensin homologue (PTEN)-deficient cancers. Despite this attractive therapeutic link, no inhibitors or antagonists of CHD1 have been reported to date. Herein, we report the discovery of UNC10142, a first-in-class small molecule antagonist of the tandem chromodomains of CHD1 that binds with an IC50 of 1.7 ± 0.2 μM. A cocrystal structure revealed a unique binding mode and competition pull-down experiments in cell lysates confirmed endogenous target engagement. Treatment of PTEN-deficient prostate cancer cells with UNC10142 led to a dose-dependent reduction in viability while PTEN-intact prostate cancer cells were unaffected, phenocopying genetic loss of CHD1. Overall, this study demonstrates the ligandability of the CHD1 chromodomains and suggests more potent and selective antagonists could translate to compounds of therapeutic value in PTEN-deficient cancers.

    Copyright © 2024 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01172.

    • TR-FRET assay platform schematic; structures of hit compounds from preliminary TR-FRET screen; structures and potencies of compounds 56 and 57; structural comparison of UNC10142 and H3K4me3 binding to CHD1; [2Fo-Fc] map of UNC10142; methyltransferase binding data; peptide pull-down validation; graphical representation of cell viability data upon 75 μM compound treatment; full Western blot images; TR-FRET assay parameters; crystallography data collection and refinement statistics; CLND solubility results; NMR and LCMS characterization of all final compounds (PDF)

    • CHD1 molecular formula strings (CSV)

    Accession Codes

    The ligand-bound co-crystal structure of UNC10142 and the tandem chromodomains of CHD1 is deposited under PDB code 8UMG. Authors will release the atomic coordinates and experimental data upon article publication.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 22, 20056–20075
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c01172
    Published November 7, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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