Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2.

Abstract

The tumor suppressor protein p53 is a potent inducer of apoptosis in transformed cells. Hdm2 is an ubiquitin ligase (E3) that acts as a major regulator of p53 by promoting its ubiquitylation and proteasomal degradation. For this reason, inhibiting the E3 activity of Hdm2 has been proposed as a therapeutic approach for cancers expressing wild-type p53. We previously identified a family of small molecules (HLI98s, 7-nitro-10-aryl-5-deazaflavins) that inhibit the E3 activity of Hdm2, increase cellular p53, and selectively kill transformed cells expressing wild-type p53. However, issues of both potency and solubility in aqueous solution limit the utility of the HLI98s. Here, we report that a highly soluble derivative of the HLI98s, which has a 5-dimethylaminopropylamino side chain but lacks the 10-aryl group (HLI373), has greater potency than the HLI98s in stabilizing Hdm2 and p53, activating p53-dependent transcription, and inducing cell death. Furthermore, we show that HLI373 is effective in inducing apoptosis of several tumor cells lines that are sensitive to DNA-damaging agents. These results suggest that HLI373 could serve as a potential lead for developing cancer therapeutics based on inhibition of the ubiquitin ligase activity of Hdm2.

• Authors: Jirouta Kitagaki, Keli K Agama, Yves Pommier, Yili Yang, Allan M Weissman
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 8 Pg. 2445-54 (Aug 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18723490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(3-dimethylaminopropylamino)-3,10-dimethyl-10H-pyrimido(4,5-b)quinoline-2,4-dione
• Aminoquinolines
• DNA Primers
• Tumor Suppressor Protein p53
• Ubiquitin
• Water
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Thymine

Topics

• Aminoquinolines (pharmacology)
• Apoptosis (drug effects)
• Base Sequence
• Cell Line, Transformed
• DNA Primers
• Humans
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Solubility
• Thymine (analogs & derivatives, pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitin (metabolism)
• Water (chemistry)