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Cancer Cell. 2012 May 15;21(5):614-25. doi: 10.1016/j.ccr.2012.03.042.

Allele-specific p53 mutant reactivation.

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1
The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.

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.

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PMID:
22624712
PMCID:
PMC3366694
DOI:
10.1016/j.ccr.2012.03.042
[Indexed for MEDLINE]
Free PMC Article

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