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Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis

Masatsugu Hiraki1, So-Young Hwang1, Shugeng Cao2

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

Chemistry & Biology
|September 1, 2015
PubMed

Insights

Chetomin (CTM) reactivates the mutant p53 R175H protein by binding to Hsp40, restoring its tumor-suppressing function. This small molecule selectively inhibits cancer cell growth, offering a novel anticancer strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The TP53 gene is frequently mutated in human cancers.
  • Reactivating mutant p53 function is a promising anticancer strategy.
  • Identifying specific small molecules to restore p53 activity is crucial.

Purpose of the Study:

  • To identify small molecules that can reactivate the mutant p53 R175H protein.
  • To investigate the mechanism by which chetomin (CTM) restores p53 function.
  • To evaluate the anticancer potential of CTM against R175H mutant p53 cancer cells.

Main Methods:

  • Conducted a high-throughput small-molecule screen using a cell-based assay.
  • Utilized in vitro and in vivo models to assess cancer cell growth inhibition.
  • Performed biochemical assays to determine the interaction between CTM, Hsp40, and p53 R175H.

Main Results:

  • Identified chetomin (CTM) as a potent reactivator of the p53 R175H mutant.
  • CTM restored p53's ability to transactivate target genes and MDM2 negative regulation.
  • CTM selectively inhibited the growth of cancer cells with the p53 R175H mutation.
  • CTM binds to Hsp40, enhancing its interaction with p53 R175H, leading to a wild-type-like conformation.

Conclusions:

  • Chetomin (CTM) specifically reactivates the p53 R175H mutant form via Hsp40.
  • CTM demonstrates significant anticancer activity against relevant cancer models.
  • These findings offer new mechanistic insights into p53 mutant reactivation for cancer therapy.

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