Get access

Structure-Guided Development of Selective RabGGTase Inhibitors

Authors

  • Dr. Robin S. Bon,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. TU Dortmund, Fakultät Chemie, 44227 Dortmund (Germany), Fax: (+49) 231-133-2499
    3. Current address: School of Chemistry and Biomedical and Health Research Centre, University of Leeds, Leeds, LS2 9JT (UK)
    Search for more papers by this author
    • These authors contributed equally.

  • Dr. Zhong Guo,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Current address: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland (Australia)
    Search for more papers by this author
    • These authors contributed equally.

  • E. Anouk Stigter,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. TU Dortmund, Fakultät Chemie, 44227 Dortmund (Germany), Fax: (+49) 231-133-2499
    Search for more papers by this author
    • These authors contributed equally.

  • Dr. Stefan Wetzel,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. TU Dortmund, Fakultät Chemie, 44227 Dortmund (Germany), Fax: (+49) 231-133-2499
    3. Current address: Quantitative Biology, Developmental and Molecular Pathways, Novartis Institutes of Biomedical Research, Basel (Switzerland)
    Search for more papers by this author
  • Dr. Sascha Menninger,

    1. Lead Discovery Center GmbH, Emil-Figge-Strasse 76a, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Dr. Alexander Wolf,

    1. Lead Discovery Center GmbH, Emil-Figge-Strasse 76a, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Dr. Axel Choidas,

    1. Lead Discovery Center GmbH, Emil-Figge-Strasse 76a, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Prof. Dr. Kirill Alexandrov,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Current address: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland (Australia)
    Search for more papers by this author
  • Dr. Wulf Blankenfeldt,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Current address: University of Bayreuth, Bayreuth (Germany)
    Search for more papers by this author
  • Prof. Dr. Roger S. Goody,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Prof. Dr. Herbert Waldmann

    Corresponding author
    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. TU Dortmund, Fakultät Chemie, 44227 Dortmund (Germany), Fax: (+49) 231-133-2499
    • Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    Search for more papers by this author

  • We thank the X-ray communities of the Max-Planck-Institut für molekulare Physiologie (Dortmund, Germany) and the Max-Planck-Institut für medizinische Forschung (Heidelberg, Germany) for collecting diffraction data at the Swiss Light Source of the Paul Scherrer Institute (Villigen, Switzerland) and for giving us generous access to and support with station X10SA. This work was supported in part by DFG grants to H.W. and R.S.G. (grant no.: SFB642), and by the Zentrum für Angewandte Chemische Genomik. R.S.B. thanks the Alexander von Humboldt Stiftung for a fellowship. E.A.S thanks the IMPRS-CB for a PhD scholarship.

Abstract

original image

Designing for selectivity: A combination of protein crystal-structure analysis, virtual screening, and synthetic chemistry has been used to develop noncytotoxic inhibitors of RabGGTase (IC50: 42 nM for the example shown; red O, blue N, yellow S) that are selective over FTase and GGTase I. Furthermore, the inhibitors display cellular activity and inhibit cancer cell proliferation.

Get access to the full text of this article

Ancillary