Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer

Drug Discov Today. 2015 Nov;20(11):1391-7. doi: 10.1016/j.drudis.2015.07.006. Epub 2015 Jul 20.


Tumor protein p53 (TP53) is the most commonly mutated gene in human cancer. The majority of mutations are missense, and generate a defective protein that is druggable. Yet, for decades, the small-molecule restoration of wild-type (WT) p53 function in mutant p53 tumors (so-called p53 mutant 'reactivation') has been elusive to researchers. The p53 protein requires the binding of a single zinc ion for proper folding, and impairing zinc binding is a major mechanism for loss of function in missense mutant p53. Here, we describe recent work defining a new class of drugs termed zinc metallochaperones that restore WT p53 structure and function by restoring Zn(2+) to Zn(2+)-deficient mutant p53.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Drug Design
  • Humans
  • Metallochaperones / metabolism
  • Mutation, Missense
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Folding / drug effects
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Zinc / metabolism


  • Antineoplastic Agents
  • Metallochaperones
  • Tumor Suppressor Protein p53
  • Zinc