Allele-Specific p53 Mutant Reactivation

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 p53R175 mutant. Mechanistic studies reveal that NSC319726 restores WT structure and function to the p53R175 mutant. This compound kills p53R172H 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 p53R175 mutant reactivator and as a lead compound for p53-targeted drug development. ► In silico screen of the NCI60 database for compounds that target mutant p53 ► Identification of two Thiosemicarbazones with activity in p53 mutant cells ► NSC319726 restores “WT”-like structure and function to the p53R175 mutant ► Zinc chelation and ROS are important for NSC319726's p53R175 mutant reactivation