Discovery of small molecule inhibitors of the MDM2-ubcH5 interaction
We will discover small molecules that disrupt the interaction between the oncoprotein MDM2 and UbcH5, its partner E2 ubiquitin conjugating enzyme. Such compounds will disrupt the E3 ligase function of MDM2 and are likely to inhibit its oncogenic functions, both those that are p53-dependent and p53-independent. The aims are: (i) to perform an in silico screen for compounds that disrupt E3-E2 interactions, and (ii) to test predicted inhibitors in high-throughput in vitro and cellular ubiquitination assays using MDM2/UbcH5. Inhibitors of the MDM2-UbcH5 interaction could ultimately be developed into novel therapeutics for sarcomas, which frequently involve amplification of the MDM2 oncogene.