2. Academic Validation
  3. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells

Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells

  • Cancer Cell. 2005 Jun;7(6):547-59. doi: 10.1016/j.ccr.2005.04.029.
Yili Yang 1,  Robert L Ludwig,  Jane P Jensen,  Shervon A Pierre,  Maxine V Medaglia,  Ilia V Davydov,  Yassamin J Safiran,  Pankaj Oberoi,  John H Kenten,  Andrew C Phillips,  Allan M Weissman,  Karen H Vousden
Affiliations

Affiliation

  • 1 Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, 1050 Boyles Street, Frederick, MD 21702, USA.
PMID: 15950904 DOI: 10.1016/j.ccr.2005.04.029
Abstract

The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and Apoptosis, although other p53-independent toxicity was also observed.

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