Oncotarget

Priority Research Papers:

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 _ and Darren R. Carpizo

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Oncotarget. 2014; 5:8879-8892. https://doi.org/10.18632/oncotarget.2432

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Abstract

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

Correspondence:

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

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.


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