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Inhibiting Hdm2 and ubiquitin-activating enzyme: targeting the ubiquitin conjugating system in cancer

A M Weissman1, Y Yang, J Kitagaki

  • 1Laboratory of Protein Dynamics and Signaling, National Cancer Institute at Frederick, P.O. Box. Bldg. 560, Frederick, MD 21702-1201, USA. amw@nih.gov

Ernst Schering Foundation Symposium Proceedings
|February 10, 2009
PubMed

Insights

Researchers identified inhibitors of Hdm2 ubiquitin ligase activity, which activate the tumor suppressor p53. These compounds show potential for cancer therapy by selectively killing cancer cells expressing wild-type p53.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The ubiquitin conjugating system offers molecular targets for disease treatment.
  • Hdm2/Mdm2, a RING finger ubiquitin ligase (E3), is overexpressed in cancers and crucial for the p53 tumor suppressor.
  • Inhibiting Hdm2 is a promising strategy for treating wild-type p53 tumors.

Purpose of the Study:

  • To identify inhibitors of Hdm2 E3 activity using high-throughput screening.
  • To evaluate the potential of identified inhibitors in activating p53 and inducing cancer cell death.
  • To explore the therapeutic potential of ubiquitin-activating enzyme (E1) inhibitors.

Main Methods:

  • High-throughput screening of small molecules and natural product extracts.
  • Utilizing both enzymatic and cell-based assays to assess Hdm2 inhibition.
  • Evaluating the impact of inhibitors on p53 response and cancer cell viability.

Main Results:

  • Identified inhibitors that block Hdm2 E3 activity.
  • Demonstrated that identified inhibitors activate p53 response and induce apoptosis.
  • Observed preferential killing of p53-expressing cancer cells and transformed cells.
  • Discovered potential ubiquitin-activating enzyme (E1) inhibitors.

Conclusions:

  • Screening for Hdm2 inhibitors is an effective method for discovering p53-activating compounds for cancer therapy.
  • Hdm2 inhibitors can selectively induce apoptosis in cancer cells.
  • E1 inhibitors represent a novel therapeutic avenue and research tools for the ubiquitin system.

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