Abstract:
:E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53-independent oncogenic effects. We developed a high-throughput cellular Mdm2 auto-ubiquitination assay, which we used to discover a class of small-molecule Mdm2 ligase activity inhibitors. These compounds inhibit Mdm2 and p53 ubiquitination in cells, reduce viability of cells with wild-type p53, and synergize with DNA-damaging agents to cause cell death. We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Herman AG,Hayano M,Poyurovsky MV,Shimada K,Skouta R,Prives C,Stockwell BRdoi
10.1158/2159-8290.CD-11-0104subject
Has Abstractpub_date
2011-09-01 00:00:00pages
312-25issue
4eissn
2159-8274issn
2159-8290pii
2159-8290.CD-11-0104journal_volume
1pub_type
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