Role of Thiol Reactivity for Targeting Mutant p53

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Reactivation of mutant p53 protein is a key strategy in cancer therapy.
• Several compounds targeting thiol groups in mutant p53 have been identified.

Purpose of the Study:

• To investigate the relationship between thiol reactivity and mutant p53 reactivation.
• To explore the potential of various chemical compounds for mutant p53 stabilization and refolding.

Main Methods:

• Analysis of the National Cancer Institute database for thiol-reactive compounds.
• Experimental evaluation of Michael acceptors, aldehydes, imines, and primary alcohols for mutant p53 activity.

Main Results:

• Michael acceptors demonstrated the highest selectivity for mutant p53-expressing cells.
• Aldehydes, imines, and primary alcohols were found to stabilize mutant p53.
• Mild thiol reactivity, especially with combined functional groups, induced mutant p53 refolding.
• Strong electrophilic activity correlated with cellular toxicity.

Conclusions:

• The study highlights the potential of Michael acceptors and related compounds for selective mutant p53 reactivation.
• Findings suggest a rational design approach for developing potent and selective mutant p53-reactivating anticancer agents.