Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism

Oncotarget. 2014 Oct 15;5(19):8879-92. doi: 10.18632/oncotarget.2432.


NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by which ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; and 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53.

Significance: We have elucidated a novel mechanism to restore wild-type structure/function to mutant p53 using small molecules functioning as zinc-metallochaperones. The pharmacologic delivery of a metal ion to restore proper folding of a mutant protein is unique to medicinal chemistry and represents a new pathway to drug mutant p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Electrophoretic Mobility Shift Assay
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Metallochaperones / metabolism
  • Metallochaperones / pharmacology*
  • Mutation
  • Protein Binding
  • Protein Folding / drug effects
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Zinc / metabolism


  • Antineoplastic Agents
  • Metallochaperones
  • NSC319726
  • Pyridines
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Zinc