Restoring PTEN function by small molecule induced deubiquitination
People
(Responsible)
Abstract
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.