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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer

Adam R Blanden1, Xin Yu2, Stewart N Loh1

  • 1Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Drug Discovery Today
|July 25, 2015
PubMed

Insights

Researchers have discovered zinc metallochaperones, a new drug class that restores wild-type (WT) p53 protein function in cancer. These drugs work by reintroducing zinc ions to deficient mutant p53, a key step in reactivating tumor suppressor activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The TP53 gene is frequently mutated in human cancers, often resulting in a defective p53 protein.
  • Missense mutations in TP53 commonly impair zinc binding, crucial for p53 protein folding and function.
  • Restoring wild-type (WT) p53 function in mutant p53 tumors has been a long-standing challenge in cancer research.

Purpose of the Study:

  • To define a novel class of small molecules, termed zinc metallochaperones, for the reactivation of mutant p53.
  • To investigate the mechanism by which zinc metallochaperones restore WT p53 structure and function.

Main Methods:

  • Characterization of a new class of drugs: zinc metallochaperones.
  • Investigating the role of zinc ion (Zn2+) restoration in mutant p53.
  • Assessing the structural and functional recovery of p53 protein.

Main Results:

  • Identified zinc metallochaperones as a new therapeutic strategy.
  • Demonstrated that these drugs restore Zn(2+) to Zn(2+)-deficient mutant p53.
  • Showed restoration of WT p53 structure and function.

Conclusions:

  • Zinc metallochaperones represent a promising new approach for targeting mutant p53 cancers.
  • Restoring zinc binding is a viable strategy for p53 reactivation.
  • This work opens new avenues for developing drugs against cancers with TP53 mutations.

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