A new study describes a compound that selectively kills cancer cells by restoring the structure and function of one of the most commonly mutated proteins in human cancer, the "tumor suppressor" p53. The research, published by Cell Press in the May 15th issue of the journal Cancer Cell, uses a novel, computer based strategy to identify potential anti-cancer drugs, including one that targets the third most common p53 mutation in human cancer, p53-R175H.
Restoring the function of mutant p53 with a drug has long been recognized as an attractive cancer therapeutic strategy," explains senior study author, Dr. Darren R. Carpizo, from The Cancer Institute of New Jersey. "However, it has proven difficult to find compounds that restore the lost function of a defective tumor-suppressor."
Using the National Cancer Institute's anticancer drug screen data researchers 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 (see structure) 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.
