title: Allele-specific p53 mutant reactivation.
abstract: Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using the National Cancer Institute's anticancer drug screen data, we identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53(R175) mutant. Mechanistic studies reveal that NSC319726 restores WT structure and function to the p53(R175) mutant. This compound kills p53(R172H) knockin mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53(R175) mutant reactivator and as a lead compound for p53-targeted drug development.
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Division of Surgical Oncology, Department of Surgery, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Institute for Advanced Study, Princeton, NJ 08540, USA; Department of Radiation Oncology and Center for Systems Biology, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Institute for Advanced Study, Princeton, NJ 08540, USA; Department of Pediatrics, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Division of Surgical Oncology, Department of Surgery, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA. Electronic address: carpizdr@umdnj.edu.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Carpizo
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011487:Protein Conformation; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000494:pharmacology*; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D013882:Thiosemicarbazones; D016159:Tumor Suppressor Protein p53; D004247:DNA; D015032:Zinc