Priority Research Papers:
Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism
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Xin Yu1,2,*, Adam R. Blanden3,*, Sumana Narayanan2, Lalithapriya Jayakumar2, David Lubin3, David Augeri4, S. David Kimball4, Stewart N. Loh3 and Darren R. Carpizo1,2
1 Rutgers Cancer Institute of New Jersey, New Jersey
2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
3 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York
4 Department of Medicinal Chemistry, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey
* These authors contributed equally to this work
Stewart N. Loh, email:
Darren R. Carpizo, email:
Keywords: mutant p53 reactivation, zinc-metallochaperone, mutant p53 targeted drug, thiosemicarbazone, reactive oxygen species (ROS)
Received: July 29, 2014 Accepted: September 02, 2014 Published: September 03, 2014
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.
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