title: Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer.
abstract: Tumor protein p53 (TP53) is the most commonly mutated gene in human cancer. The majority of mutations are missense, and generate a defective protein that is druggable. Yet, for decades, the small-molecule restoration of wild-type (WT) p53 function in mutant p53 tumors (so-called p53 mutant 'reactivation') has been elusive to researchers. The p53 protein requires the binding of a single zinc ion for proper folding, and impairing zinc binding is a major mechanism for loss of function in missense mutant p53. Here, we describe recent work defining a new class of drugs termed zinc metallochaperones that restore WT p53 structure and function by restoring Zn(2+) to Zn(2+)-deficient mutant p53.
authors.affiliation: Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Blanden
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Stewart N
authors.initials: SN
authors.lastname: Loh
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Institute for Advanced Study, Princeton, NJ 08540, USA.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA. Electronic address: carpizdr@cinj.rutgers.edu.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Carpizo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D056511:Metallochaperones / Q000378:metabolism; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056511:Metallochaperones; D016159:Tumor Suppressor Protein p53; D015032:Zinc