Syringolin A Selectively Labels the 20 S Proteasome in Murine EL4 and Wild-Type and Bortezomib-Adapted Leukaemic Cell Lines

Authors

  • Jérôme Clerc,

    1. Chemical Genomics Centre der Max-Planck-Gesellschaft, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany), Fax: (+49) 231-9742-6479
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  • Bogdan I. Florea,

    1. Leiden Institute of Chemistry and Netherlands Proteomics Centre, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden (The Netherlands)
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  • Marianne Kraus,

    1. Cantonal Hospital St. Gallen, Laboratory for Experimental Oncology, Rorschacherstrasse 95, 9007 St. Gallen (Switzerland)
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  • Michael Groll Prof. Dr.,

    1. Centre for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)
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  • Robert Huber Prof. Dr.,

    1. Max-Planck-Institut für Biochemie, Am Klopferspitz 18 a, 82152 Martinsried (Germany)
    2. Zentrum für Medizinische Biotechnologie, Universität Duisburg–Essen, 45117 Essen (Germany)
    3. School of Biosciences, Cardiff University, Cardiff CF10 3US (UK)
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  • André S. Bachmann Prof. Dr.,

    1. Cancer Research Center of Hawaii, University of Hawaii at Manoa, 1236 Lauhala Street, 96813 Honolulu, Hawaii (USA)
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  • Robert Dudler Prof. Dr.,

    1. Zürich–Basel Plant Science Centre, Institute of Plant Biology, Universität Zürich, Zollikerstrasse 107, 8008 Zürich (Switzerland)
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  • Christoph Driessen Prof. Dr.,

    1. Cantonal Hospital St. Gallen, Laboratory for Experimental Oncology, Rorschacherstrasse 95, 9007 St. Gallen (Switzerland)
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  • Herman S. Overkleeft Prof. Dr.,

    1. Leiden Institute of Chemistry and Netherlands Proteomics Centre, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden (The Netherlands)
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  • Markus Kaiser Dr.

    1. Chemical Genomics Centre der Max-Planck-Gesellschaft, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany), Fax: (+49) 231-9742-6479
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Abstract

The natural product syringolin A (SylA) is a potent proteasome inhibitor with promising anticancer activities. To further investigate its potential as a lead structure, selectivity profiling with cell lysates was performed. At therapeutic concentrations, a rhodamine-tagged SylA derivative selectively bound to the 20 S proteasome active sites without detectable off-target labelling. Additional profiling with lysates of wild-type and bortezomib-adapted leukaemic cell lines demonstrated the retention of this proteasome target and subsite selectivity as well as potency even in clinically relevant cell lines. Our studies, therefore, propose that further development of SylA might indeed result in an improved small molecule for the treatment of leukaemia.

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