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

• Published in: Molecular cancer therapeutics Vol. 7; no. 8; pp. 2445 - 2454
• Main Authors: Kitagaki, Jirouta, Agama, Keli K, Pommier, Yves, Yang, Yili, Weissman, Allan M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.08.2008
• Subjects: Aminoquinolines - pharmacology; apoptosis; Apoptosis - drug effects; Base Sequence; cancer therapeutics; Cell Line, Transformed; DNA Primers; Hdm2/Mdm2; Humans; p53; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Solubility; Thymine - analogs & derivatives; Thymine - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; ubiquitin; Ubiquitin - metabolism; Water - chemistry
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0063

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. [Mol Cancer Ther 2008;7(8):2445–54]