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Inhibiting Hdm2 and Ubiquitin-Activating Enzyme: Targeting the Ubiquitin Conjugating System in Cancer

  • A. M. Weissman
  • Y. Yang
  • J. Kitagaki
  • C. A. Sasiela
  • J. A. Beutler
  • B. R. O'Keefe
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2008/1)

Abstract

The ubiquitin conjugating system represents a rich source of potential molecular targets for cancer and other diseases. One target of great interest is the RING finger ubiquitin ligase (E3) Hdm2/Mdm2, which is frequently overexpressed in cancer and is a critical E3 for the tumor suppressor p53. For those 50% of tumors that express wild-type p53, agents that inhibit Hdm2 have great potential clinical utility. We summarize our ongoing efforts to identify inhibitors of Hdm2 E3 activity by high-throughput screening of both defined small molecules and natural product extracts. Employing a strategy using both enzymatic and cell-based assays, we have identified inhibitors that block the E3 activity of Hdm2, activate a p53 response, preferentially kill p53-expressing cells, and have the capacity to differentially cause death of transformed cells. Therefore, screening for inhibitors of Hdm2 ubiquitin ligase activity through in vitro assays represents a powerful means of identifying molecules that activate p53 in cancer cells to induce apoptosis. We also discuss the potential of inhibitors of ubiquitin-activating enzyme (E1) that were discovered during these screens. E1 inhibitors may similarly serve as the basis for novel therapeutics. Additionally, they represent unique tools for providing new insights into the ubiquitin conjugating system.

Keywords

Ubiquitin Ligase Proteasome Inhibitor Ring Finger Ubiquitin Ligase Activity Potential Molecular Target 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank our collaborators at the National Cancer Institute, the Beatson Institute for Cancer Research, and at Meso Scale Discovery. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and by the Japanese Society for the Promotion of Science.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • A. M. Weissman
    • 1
  • Y. Yang
    • 1
  • J. Kitagaki
    • 1
  • C. A. Sasiela
    • 2
  • J. A. Beutler
    • 2
  • B. R. O'Keefe
    • 2
  1. 1.Laboratory of Protein Dynamics and SignalingNational Cancer Institute at FrederickFrederickUSA
  2. 2.Molecular Targets Development ProgramNational Cancer Institute at FrederickFrederickUSA

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