Restoring PTEN function by small molecule induced deubiquitination

Years of investigations identified the Phosphatase and tensing homolog (PTEN) as one of the most frequently

disrupted tumor suppressors in cancer. Moreover, PTEN deficiency is also the root cause of a severe and

invalidating 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 crucial

activity of E3 ligase enzymes. At the same time, scientific literature reported about the role of some

deubiquitinases that antagonize the inactivation/degradation process. The identification of therapeutics which

administration 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 unselective

molecules were reported in literature so far.

In this project, we propose to apply a high-throughput screening protocol based on the use of DNA encoded

libraries, to identify small molecules (molecular glues) able to induce and/or reinforce the interaction between

PTEN and two deubiquitinases (USP10 and USP13), that have already proved to be able to restore or reactivate

the PTEN function in cancer cells.

The drug discovery strategy proposed in this project can lead to the rapid identification of small molecules

able 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 of

modulators of protein-protein interaction.