New Strategies for Mutant Rescue of the Tumor Suppressor p53 through Covalent Warheads

Abstract

Die Dissertation ist gesperrt bis zum 19. September 2026 !

The tumor suppressor protein p53, also known as the “guardian of the genome,” plays a pivotal role in the cell cycle. In many human cancer types, a mutation of p53 is found. The structural ß-sandwich mutant Y220C is the ninth most common p53 mutant, which has a solvent-accessible hydrophobic cleft. The Y220C mutant is markedly thermodynamically destabilized. The melting temperature is reduced by approximately 8 °C, leading to rapid denaturation and aggregation at body temperature. Therefore, this thesis aimed to identify compounds that target and stabilize p53 and its mutants using fragment-based approaches, specifically for the thermosensitive p53-Y220C mutant with halogen bonding in the pocket or covalent modification of the Cys220 residue.