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Updated: May 28, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Pestones A and B from a Fungus Pestalotiopsis sp. Bound to Mutant p53 and Changed Its Conformation

Yusaku Sadahiro1, Misaki Okubo1, Yuki Hitora1

  • 1Department of Natural Medicines, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.

Journal of Natural Products
|February 14, 2025
PubMed

Insights

Researchers discovered new compounds, pestones A and B, from the fungus *Pestalotiopsis* sp. These compounds reactivate mutant p53 (a cancer target) and show potent anticancer activity, offering a promising new cancer therapy strategy.

Area of Science:

  • Natural Products Chemistry
  • Cancer Biology
  • Drug Discovery

Background:

  • Oncogenic mutant p53 is a key target in cancer therapy.
  • Developing drugs to reactivate mutant p53 is a promising therapeutic strategy.
  • Fungal extracts represent a potential source for novel anticancer agents.

Purpose of the Study:

  • To isolate and characterize compounds from *Pestalotiopsis* sp. with the ability to restore mutant p53 function.
  • To evaluate the anticancer potential of isolated compounds against p53-mutated cancer cells.
  • To investigate the mechanism of action of these compounds on mutant p53.

Main Methods:

  • Bioassay-guided purification of *Pestalotiopsis* sp. extract.
  • Spectroscopic analysis (NMR, MS) for structural elucidation.
  • Cellular thermal shift assay (CETSA) and immunofluorescence staining to assess p53 interaction.
  • Cytotoxicity assays (IC50 determination) and flow cytometry for apoptosis analysis.
  • In vivo tumor growth inhibition studies in a mouse model.

Main Results:

  • Isolation of two new dimeric epoxyquinoids, pestones A (1) and B (2), and known compound rosnecatrone (3).
  • Pestones A and B were confirmed to alter mutant p53 conformation and compound 1 directly binds to mutant p53, increasing its thermostability.
  • Compounds 1 and 2 demonstrated significant cytotoxic activity against Saos-2 (p53R175H) cells (IC50 values 1.0 and 1.1 μM).
  • Compound 1 induced apoptosis in cancer cells and reduced tumor growth in vivo.

Conclusions:

  • Pestones A and B are novel dimeric epoxyquinoids with the ability to reactivate mutant p53.
  • These compounds exhibit potent anticancer activity through mechanisms involving p53 restoration, apoptosis induction, and tumor growth inhibition.
  • Pestalotiopsis sp. derived compounds represent a promising new avenue for developing targeted cancer therapies against p53-mutated cancers.

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