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 language | English (US) |
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Pages (from-to) | 8879-8892 |
Number of pages | 14 |
Journal | Oncotarget |
Volume | 5 |
Issue number | 19 |
DOIs | |
State | Published - 2014 |
Externally published | Yes |
Keywords
- Mutant p53 reactivation
- Mutant p53 targeted drug
- Reactive oxygen species (ROS)
- Thiosemicarbazone
- Zinc-metallochaperone
ASJC Scopus subject areas
- Oncology