2. Academic Validation
  3. Allele-specific p53 mutant reactivation

Allele-specific p53 mutant reactivation

  • Cancer Cell. 2012 May 15;21(5):614-625. doi: 10.1016/j.ccr.2012.03.042.
Xin Yu 1,  Alexei Vazquez 2,  Arnold J Levine 3,  Darren R Carpizo 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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: [email protected].
PMID: 22624712 DOI: 10.1016/j.ccr.2012.03.042
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18634
    99.02%, MDM-2/p53 p53 Activator