Restoring PTEN function by small molecule induced deubiquitination

Years of investigations identified the Phosphatase and tensing homolog (PTEN) as one of the most frequentlydisrupted tumor suppressors in cancer. Moreover, PTEN deficiency is also the root cause of a severe andinvalidating group of genetically related disorders characterized by the presence of small tumors (hamartomas)and, therefore, indicated as PTEN hamartoma syndrome (PTHS).Recent studies have demonstrated that PTEN can be inactivated or degraded via ubiquitination by the crucialactivity of E3 ligase enzymes. At the same time, scientific literature reported about the role of somedeubiquitinases that antagonize the inactivation/degradation process. The identification of therapeutics whichadministration results in PTEN restoring/reactivation could be a huge breakthrough in cancer therapy. However,because of the complexity of the molecular pathways that regulate PTEN, only few inefficient and unselectivemolecules were reported in literature so far.In this project, we propose to apply a high-throughput screening protocol based on the use of DNA encodedlibraries, to identify small molecules (molecular glues) able to induce and/or reinforce the interaction betweenPTEN and two deubiquitinases (USP10 and USP13), that have already proved to be able to restore or reactivatethe PTEN function in cancer cells.The drug discovery strategy proposed in this project can lead to the rapid identification of small moleculesable to restore/reactivate PTEN that can be immediately evaluated for their anticancer properties. Moreover,the project activities can help to define an efficient strategy to be used in larger context of the discovery ofmodulators of protein-protein interaction.