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

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URI: http://hdl.handle.net/10900/158730
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1587302
http://nbn-resolving.org/urn:nbn:de:bsz:21-dspace-1587303
http://dx.doi.org/10.15496/publikation-100062
Dokumentart: PhDThesis
Date: 2026-09-17
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Pharmazie
Advisor: Böckler, Frank M. (Prof. Dr.)
Day of Oral Examination: 2024-09-17
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Protein p53
Other Keywords:
p53-Y220C
covalent fragment-based drug discovery
warheads
DSF
FPA
intact protein MS
X-ray crystallography
halogen bonding
License: http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=en
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Inhaltszusammenfassung:

Die Dissertation ist gesperrt bis zum 19. September 2026 !

Abstract:

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.

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