Discovery of compounds that reactivate p53 mutants in vitro and in vivo

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The p53 protein is a crucial tumor suppressor frequently inactivated by mutations in human cancers.
• Missense mutations in the DNA binding domain are common, leading to loss of tumor suppressor function.
• Restoring p53 function presents a significant therapeutic opportunity for various cancers.

Purpose of the Study:

• To identify small molecules capable of reactivating mutant p53.
• To demonstrate the feasibility of a computational drug discovery approach for p53 mutations.

Main Methods:

• Utilized virtual screening to identify potential p53-reactivating compounds.
• Investigated the UCI-LC0023 compound series for its effects on mutant p53.
• Assessed compound binding, conformational changes, chromatin association, DNA binding, and transcriptional activity in vitro and in vivo.

Main Results:

• Identified UCI-LC0023 compounds that bind to mutant p53 and induce conformational changes.
• Demonstrated restoration of chromatin association and sequence-specific DNA binding for p53 mutants.
• Showed induction of p53-dependent transcription and inhibition of tumor progression in mutant p53 models.
• Confirmed specificity for mutant p53, with no effect on p53-null or wild-type p53.

Conclusions:

• A computational strategy successfully identified small molecules that reactivate mutant p53.
• The UCI-LC0023 series shows potential as corrector drugs for p53 hotspot mutations.
• This approach validates the use of computation-guided drug discovery for targeting p53 in cancer therapy.