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Research ArticleArticle

P6981, An Arylstibonic Acid, Is a Novel Low Nanomolar Inhibitor of cAMP Response Element-Binding Protein Binding to DNA

Jianfei Zhao, Jason R. Stagno, Lyuba Varticovski, Eric Nimako, Vikas Rishi, Kathy McKinnon, Rhone Akee, Robert H. Shoemaker, Xinhua Ji and Charles Vinson
Molecular Pharmacology November 2012, 82 (5) 814-823; DOI: https://doi.org/10.1124/mol.112.080820
Jianfei Zhao
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Jason R. Stagno
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Lyuba Varticovski
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Eric Nimako
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Vikas Rishi
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Kathy McKinnon
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Rhone Akee
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Robert H. Shoemaker
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Xinhua Ji
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Charles Vinson
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (J.Z., E.N., V.R., C.V.); Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, Maryland (J.R.S., X.J.); Laboratory of Receptor Biology and Gene Expression, Vaccine Branch, National Cancer Institute, Bethesda, Maryland (L.V., K.M.); Natural Products Support Group, SAIC-Frederick, Frederick, Maryland (R.A.); and Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland (R.H.S.)
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Abstract

Several basic leucine zipper (B-ZIP) transcription factors have been implicated in cancer, substance abuse, and other pathological conditions. We previously identified arylstibonic acids that bind to B-ZIP proteins and inhibit their interaction with DNA. In this study, we used electrophoretic mobility shift assay to analyze 46 arylstibonic acids for their activity to disrupt the DNA binding of three B-ZIP [CCAAT/enhancer-binding protein α, cyclic AMP-response element-binding protein (CREB), and vitellogenin gene-binding protein (VBP)] and two basic helix-loop-helix leucine zipper (B-HLH-ZIP) [USF (upstream stimulating factor) and Mitf] proteins. Twenty-five arylstibonic acids showed activity at micromolar concentrations. The most active compound, P6981 [2-(3-stibonophenyl)malonic acid], had half-maximal inhibition at ∼5 nM for CREB. Circular dichroism thermal denaturation studies indicated that P6981 binds both the B-ZIP domain and the leucine zipper. The crystal structure of an arylstibonic acid, NSC13778, bound to the VBP leucine zipper identified electrostatic interactions between both the stibonic and carboxylic acid groups of NSC13778 [(E)-3-(3-stibonophenyl)acrylic acid] and arginine side chains of VBP, which is also involved in interhelical salt bridges in the leucine zipper. P6981 induced GFP-B-ZIP chimeric proteins to partially localize to the cytoplasm, demonstrating that it is active in cells. P6981 inhibited the growth of a patient-derived clear cell sarcoma cell line whose oncogenic potential is driven by a chimeric protein EWS-ATF1 (Ewing's sarcoma protein-activating transcription factor 1), which contains the DNA binding domain of ATF1, a B-ZIP protein. NSC13778 inhibited the growth of xenografted clear cell sarcoma, and no toxicity was observed. These experiments suggest that antimony containing arylstibonic acids are promising leads for suppression of DNA binding activities of B-ZIP and B-HLH-ZIP transcription factors.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Intramural Research Program of the Center for Cancer Research, National Institutes of Health National Cancer Institute.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080820.

  • ABBREVIATIONS:

    B-ZIP
    basic leucine zipper
    B-HLH-ZIP
    basic helix-loop-helix leucine zipper
    LZ
    leucine zipper
    CREB
    cyclic AMP-response element-binding protein
    EMSA
    electrophoretic mobility shift assay
    C/EBP
    CCAAT/enhancer-binding protein
    VBP
    vitellogenin gene-binding protein
    CCS-1
    clear cell sarcoma cell line
    Mitf
    microphthalamia-associated transcription factor
    USF
    upstream stimulating factor
    DTT
    dithiothreitol
    CD
    circular dichroism
    GFP
    green fluorescent protein
    GR
    glucocorticoid receptor
    Ape1
    apurinic/apyrimidinic endonuclease 1
    EWS
    Ewing's sarcoma protein
    P6981
    2-(3-stibonophenyl)malonic acid
    NSC13778
    (E)-3-(3-stibonophenyl)acrylic acid
    ATF
    activating transcription factor.

  • Received June 26, 2012.
  • Accepted July 27, 2012.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

P6981 Inhibits DNA Binding of B-ZIP

Jianfei Zhao, Jason R. Stagno, Lyuba Varticovski, Eric Nimako, Vikas Rishi, Kathy McKinnon, Rhone Akee, Robert H. Shoemaker, Xinhua Ji and Charles Vinson
Molecular Pharmacology November 1, 2012, 82 (5) 814-823; DOI: https://doi.org/10.1124/mol.112.080820

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Research ArticleArticle

P6981 Inhibits DNA Binding of B-ZIP

Jianfei Zhao, Jason R. Stagno, Lyuba Varticovski, Eric Nimako, Vikas Rishi, Kathy McKinnon, Rhone Akee, Robert H. Shoemaker, Xinhua Ji and Charles Vinson
Molecular Pharmacology November 1, 2012, 82 (5) 814-823; DOI: https://doi.org/10.1124/mol.112.080820
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