Drug discovery and mutant p53

Area of Science:

• Oncology
• Molecular Biology
• Biophysics

Background:

• Missense mutations in the p53 tumor suppressor gene are frequent in human cancers.
• These mutations inactivate p53's tumor-suppressive functions but can stabilize a pro-oncogenic mutant p53 protein.
• Understanding mutant p53's role is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To review recent multidisciplinary advances in targeting the mutant p53 pathway.
• To highlight novel strategies for refolding and reactivating mutant p53.
• To explore the pro-oncogenic signaling and interactome of mutant p53.

Main Methods:

• Biophysical modeling to understand p53 inactivation mechanisms.
• Analysis of mutant p53 protein stability and degradation pathways (e.g., MDM2-mediated).
• Mapping the mutant p53 interactome to identify oncogenic signaling networks.

Main Results:

• Biophysical models explain p53 mutation-induced inactivation.
• Mutant p53 can evade degradation, contributing to its oncogenic potential.
• The mutant p53 interactome reveals its role in diverse oncogenic and pro-metastatic signaling.

Conclusions:

• Therapeutic targeting of mutant p53 pathways shows significant promise.
• Advances in understanding mutant p53's function facilitate drug discovery.
• Focus on protein-protein interactions and conformational control is key for targeting mutant p53.