Computational design of novel PROTAC structures targeting the p53 mutants for degradation.

The object of this thesis is the p53 protein, a tumor suppressor able to respond to various types of chemical and physical cellular stress by leading to mechanisms such as DNA repair, cell cycle arrest and apoptosis. Unfortunately, the transcription factor p53 gets mutated in nearly 50% of human cancer cells, resulting in the inactivation of the protein which will be unable to exercise its proper functions. Therefore, this leads to a facilitated cancer progression and negative consequences for patients. Studies identified in the protein’s DNA core domain six "hot spot" mutations, of which this thesis deals with the G245S one, a point mutation of the glycine in position 245 into a serine residue. Until now, what has been done was trying to reactivate the mutants in order to restore the wild type activity. However, the results achieved have been either unsuccessful or are still under development. Therefore, this thesis aims to explore a new strategy that consists in targeting specifically the mutant G245S-p53 in order to destroy it by means of Proteolysis- targeting chimeras (PROTACs). These are bifunctional small molecules able to target a protein for its degradation by taking advantage of the human proteolitic system. This computational study is the first one to explore and propose PROTACs for the mutant p53 degradation. Currently, these structures are being synthesized for in-vitro experiments and, hopefully, they will be tested for treatment too.