title: Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Jersey. Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. These authors contributed equally to this work.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York. These authors contributed equally to this work.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Blanden
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
authors.forename: Sumana
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
authors.forename: Lalithapriya
authors.initials: L
authors.lastname: Jayakumar
authors.affiliation: Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York.
authors.forename: David
authors.initials: D
authors.lastname: Lubin
authors.affiliation: Department of Medicinal Chemistry, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Augeri
authors.affiliation: Department of Medicinal Chemistry, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey.
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.affiliation: Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Stewart N
authors.initials: SN
authors.lastname: Loh
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Jersey. Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Carpizo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D056511:Metallochaperones / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056511:Metallochaperones; C000600074:NSC319726; D011725:Pyridines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D015032:Zinc