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

Xin Yu, Adam R. Blanden, Sumana Narayanan, Lalithapriya Jayakumar, David Lubin, David Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8879-8892
Number of pages14
JournalOncotarget
Volume5
Issue number19
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Mutant p53 reactivation
  • Mutant p53 targeted drug
  • Reactive oxygen species (ROS)
  • Thiosemicarbazone
  • Zinc-metallochaperone

ASJC Scopus subject areas

  • Oncology

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