Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2.
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.
Kitagaki
Jirouta
J
Laboratory of Protein Dynamics and Signaling, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA.
Agama
Keli K
KK
Pommier
Yves
Y
Yang
Yili
Y
Weissman
Allan M
AM
D000634:Aminoquinolines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002461:Cell Line, Transformed; D017931:DNA Primers; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014867:Water / Q000737:chemistry*
C532368:5-(3-dimethylaminopropylamino)-3,10-dimethyl-10H-pyrimido(4,5-b)quinoline-2,4-dione; D000634:Aminoquinolines; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D014867:Water; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D013941:Thymine