Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Missense mutations in p53 are common in human cancers, leading to protein aggregation and loss of function.
• Mutant p53 aggregates form amyloid-like structures in the cytosol, contributing to cancer progression.
• Existing therapies often lack specificity and can cause significant side effects.

Purpose of the Study:

• To identify small molecules that inhibit mutant p53 aggregation.
• To evaluate the therapeutic potential of identified inhibitors in preclinical cancer models.
• To investigate the mechanism of action of these inhibitors.

Main Methods:

• Screening of an oligopyridylamide library for inhibitors of mutant p53 aggregation.
• In vitro assays to assess inhibition of amyloid formation by ADH-6.
• In cellulo studies using human cancer cells to evaluate aggregate dissociation and functional restoration.
• In vivo studies using xenograft models to assess anti-tumor efficacy and toxicity.

Main Results:

• A tripyridylamide, ADH-6, was identified that inhibits the self-assembly of mutant p53 DNA-binding domain (DBD).
• ADH-6 dissociates existing mutant p53 aggregates in cancer cells, restoring p53 transcriptional activity.
• Treatment with ADH-6 induced cell cycle arrest and apoptosis in cancer cells.
• ADH-6 treatment led to significant tumor shrinkage in xenograft models with no observed toxicity in healthy tissues.

Conclusions:

• Small-molecule amyloid inhibitors can be repurposed as potent anticancer agents.
• ADH-6 effectively targets and neutralizes oncogenic mutant p53 aggregates.
• This study presents a promising new therapeutic strategy for cancers harboring mutant p53.