| Autor: |
Kitagaki J; Laboratory of Protein Dynamics and Signaling, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA., Agama KK, Pommier Y, Yang Y, Weissman AM |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular cancer therapeutics [Mol Cancer Ther] 2008 Aug; Vol. 7 (8), pp. 2445-54. |
| DOI: |
10.1158/1535-7163.MCT-08-0063 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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