Allele-Specific p53 Mutant Reactivation
Copyright policy )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 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.
- Institute for Advanced Study United States
- Rutgers Cancer Institute United States
- University of Medicine and Dentistry of New Jersey United States
Cancer Research, Cell Survival, Mutation, Missense, Mice, Nude, Antineoplastic Agents, Apoptosis, Mice, Transgenic, Cell Line, Mice, Neoplasms, Animals, Humans, Gene Knock-In Techniques, Alleles, Chelating Agents, Mice, Inbred BALB C, Binding Sites, Dose-Response Relationship, Drug, Cell Biology, DNA, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Oncology
Cancer Research, Cell Survival, Mutation, Missense, Mice, Nude, Antineoplastic Agents, Apoptosis, Mice, Transgenic, Cell Line, Mice, Neoplasms, Animals, Humans, Gene Knock-In Techniques, Alleles, Chelating Agents, Mice, Inbred BALB C, Binding Sites, Dose-Response Relationship, Drug, Cell Biology, DNA, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Oncology
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