Boron-Based Inhibitors of Acyl Protein Thioesterases 1 and 2

Authors

  • Dr. Tobias J. Zimmermann,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Faculty of Chemistry, Technical University of Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • Marco Bürger,

    1. Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • Prof. Dr. Etsu Tashiro,

    1. Bioprobe Application Team, RIKEN-Max Planck Joint Research Center, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
    2. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
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  • Dr. Yasumitsu Kondoh,

    1. Chemical Biology Core Facility, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
    2. Bioprobe Application Team, RIKEN-Max Planck Joint Research Center, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Nancy E. Martinez,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Faculty of Chemistry, Technical University of Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
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  • Dr. Kristina Görmer,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Faculty of Chemistry, Technical University of Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
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  • Sigrid Rosin-Steiner,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dr. Takeshi Shimizu,

    1. Chemical Biology Core Facility, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Dr. Shoichiro Ozaki,

    1. Developmental Neurobiology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Dr. Katsuhiko Mikoshiba,

    1. Developmental Neurobiology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Dr. Nobumoto Watanabe,

    1. Chemical Biology Core Facility, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
    2. Bioprobe Application Team, RIKEN-Max Planck Joint Research Center, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Prof. Dr. Dennis Hall,

    1. Department of Chemistry, Edmonton, Gunning–Lemieux, Chemistry Centre, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada)
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  • Dr. Ingrid R. Vetter,

    1. Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Prof. Dr. Hiroyuki Osada,

    Corresponding author
    1. Chemical Biology Core Facility, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
    2. Bioprobe Application Team, RIKEN-Max Planck Joint Research Center, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
    • Chemical Biology Core Facility, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
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  • Dr. Christian Hedberg,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Faculty of Chemistry, Technical University of Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
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  • Prof. Dr. Herbert Waldmann

    Corresponding author
    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Faculty of Chemistry, Technical University of Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
    • Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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Abstract

Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly.

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