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Hydroxyureas as Noncovalent Proteasome Inhibitors

Authors


  • We acknowledge the contributions of and helpful discussions with Dr. J. Vidal, Dr. A. Tuch, and Dr. P. Schreier (staff members of Bayer CropScience). We are grateful to R. Feicht for large-scale purification of yeast 20S proteasomes, to O. Ackermann for conducting HPLC analyses, and the staff of the PXI beamline at the Paul Scherrer Institute, Swiss Light Source, Villigen, Switzerland, for help during data collection. We also thank two students in our lab, Martina Muller and Christian Dubiella, for their help. This work was supported by SFB 594–A 11 (M.G.) and a DAAD-CONACYT scholarship (M.A.).

Abstract

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Inhibitors with a new mechanism of action are needed for 20S proteasome (CP) inhibition owing to the ineffectiveness of current market drugs against some types of solid tumors. A novel class of nonpeptidic CP inhibitors has been developed, which display reversible and noncovalent binding. The structure-based design of these highly active and site-specific inhibitors revealed unexplored binding subpockets.

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