Allele-specific p53 mutant reactivation

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Mutant p53 protein accumulation is common in many cancers.
• Restoring wild-type (WT) p53 function presents a promising cancer therapeutic strategy.
• Targeting specific p53 mutations, like R175, is crucial for effective treatment.

Purpose of the Study:

• To identify compounds that can rescue the function of mutant p53.
• To evaluate the efficacy of thiosemicarbazone derivatives against mutant p53 cancer cells.
• To investigate the mechanism of action for identified compounds.

Main Methods:

• Screening of the National Cancer Institute's anticancer drug library.
• In vitro growth inhibition assays in mutant p53 cell lines.
• In vivo studies using p53(R172H) knockin mice and xenograft models.
• Mechanistic studies involving zinc chelation and redox analysis.

Main Results:

• Two thiosemicarbazone compounds showed enhanced growth inhibition in mutant p53 cells, especially the R175 mutant.
• NSC319726 was identified as a potent reactivator of the p53(R175) mutant's WT structure and function.
• NSC319726 demonstrated in vivo efficacy by inducing apoptosis in mice and inhibiting tumor growth in a mutant p53-dependent manner.
• The compound's activity relies on its zinc-chelating properties and ability to induce redox changes.

Conclusions:

• NSC319726 is a novel p53(R175) mutant reactivator.
• This compound serves as a lead for developing p53-targeted cancer therapies.
• The findings highlight the therapeutic potential of targeting mutant p53 using specific chemical compounds.