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Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2020, 11, 10, 1913-1918
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    Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα
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    • James R. Annand
      James R. Annand
      Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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    • Andrew R. Henderson
      Andrew R. Henderson
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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    • Kyle S. Cole
      Kyle S. Cole
      Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
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    • Aaron J. Maurais
      Aaron J. Maurais
      Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
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    • Jorge Becerra
      Jorge Becerra
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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    • Yejun Liu
      Yejun Liu
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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    • Eranthie Weerapana
      Eranthie Weerapana
      Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
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      Orcidhttp://orcid.org/0000-0002-0835-8301
    • Angela N. Koehler
      Angela N. Koehler
      David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States
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    • Anna K. Mapp
      Anna K. Mapp
      Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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      Orcidhttp://orcid.org/0000-0003-0791-8327
    • Corinna S. Schindler*
      Corinna S. Schindler
      Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
      Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
      *Tel: 764-763-6853. Email: [email protected]
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      Orcidhttp://orcid.org/0000-0003-4968-8013
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2020, 11, 10, 1913–1918
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    https://doi.org/10.1021/acsmedchemlett.9b00613
    Published May 21, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    The small molecule gibberellin JRA-003 was identified as an inhibitor of the NF-kB (nuclear kappa-light-chain-enhancer of activated B cells) pathway. Here we find that JRA-003 binds to and significantly inhibits the nuclear translocation of pathway-activating kinases IKKα (IκB kinase alpha) and IKKβ (IκB kinase beta). Analogs of JRA-003 were synthesized and NF-κB-inhibiting gibberellins were found to be cytotoxic in cancer-derived cell lines (HS 578T, HCC 1599, RC-K8, Sud-HL4, CA 46, and NCIH 4466). Not only was JRA-003 identified as the most potent synthetic gibberellin against cancer-derived cell lines, it displayed no cytotoxicity in cells derived from noncancerous sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity suggests a promising approach for the development of new therapeutics.

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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/acsmedchemlett.9b00613.

    • Supplemental figures and tables, experimental conditions, and synthesis and characterization of all compounds (PDF)

    • Proteins detected by mass spectroscopy after pull down with JRA-031 or negative control and complete readout of the proteome-wide SILAC mass spectrometry screen (XLSX)

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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2020, 11, 10, 1913–1918
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.9b00613
    Published May 21, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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