Allele-Specific p53 Mutant Reactivation

The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Cancer cell (Impact Factor: 23.52). 05/2012; 21(5):614-25. DOI: 10.1016/j.ccr.2012.03.042
Source: PubMed

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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Available from: Alexei Vazquez, Jul 21, 2014
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    • "If ZMC1 is a Zn 21 ionophore and the source of the Zn 21 it delivers is extracellular, as suggested by our kinetic experiments in Zn 21 -free media, then depleting the extracellular Zn 21 from complete media should inhibit ZMC1's function. To test this prediction, we took advantage of ZMC1's known ability to induce a conformational change in p53- R175H using the conformation specific antibodies PAB240 and PAB1620 in complete media with and without Zn 21 chelators (Fig. 5A) (Yu et al., 2012). Consistent with previous results, ZMC1 treatment shifted the p53-R175H immunophenotype from misfolded (PAB240) to WT-like (PAB1620) in TOV112D cells in untreated media (Yu et al., 2012). "
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    ABSTRACT: p53 is a Zn(2+)-dependent tumor suppressor inactivated in >50% of human cancers. The most common mutation, R175H, inactivates p53 by reducing its affinity for the essential zinc ion, leaving the mutant protein unable to bind the metal in the low [Zn(2+)]free environment of the cell. The exploratory cancer drug ZMC1 was previously demonstrated to reactivate this and other Zn(2+)-binding mutants by binding Zn(2+) and buffering it to a level such that Zn(2+) can repopulate the defective binding site, but how it accomplishes this in the context of living cells and organisms is unclear. Here, we demonstrate that ZMC1 increases intracellular [Zn(2+)]free by functioning as a zinc ionophore. ZMC1 binds Zn(2+) in the extracellular environment, diffuses across the plasma membrane as the neutral complex, and releases zinc into the cell once again as the Zn(2+) ion. It raises intracellular [Zn(2+)]free in cancer (TOV112D) and non-cancer (HEK293) cell lines to 15.8 and 18.1 nM, respectively, with half times of 2-3 min. These [Zn(2+)]free are predicted to result in ~90% saturation of p53-R175H, thus accounting for its observed reactivation. This mechanism is supported by the x-ray crystal structure of the [Zn(ZMC1)2] complex, which demonstrates structural and chemical features consistent with those of known metal ionophores. These findings provide a physical mechanism linking ZMC1's in vitro and in vivo activities, and define the remaining critical parameter necessary for developing synthetic metallochaperones for clinical use. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 02/2015; 87(5). DOI:10.1124/mol.114.097550 · 4.13 Impact Factor
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    • "This may help trigger a pro-oxidant function in p53 upon application of a mutant p53 reactivating drug. This was demonstrated for the p53 reactivating thiosemicarbazone NSC319726 [32]. "
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    ABSTRACT: Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.
    Apoptosis 04/2014; 19(7). DOI:10.1007/s10495-014-0990-3 · 3.69 Impact Factor
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    • "The potential use of zinc to recover wild-type folding has therefore been explored and this approach has been shown to restore chemosensitivity to anticancer drugs in cells expressing endogenous mutant p53 (Puca et al., 2011). In addition, the thiosemicarbazone metal ion chelator NSC31926 was found to restore wild-type function in a variety of different mutant p53-expressing cell lines, possibly through increasing the bioavailability of zinc to (mutant) p53 (Yu et al., 2012). Of all the compounds that restore wild-type activity, the most progress has been made with PRIMA-1 analogs, with the "
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    ABSTRACT: Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types.
    Cancer cell 03/2014; 25(3):304-317. DOI:10.1016/j.ccr.2014.01.021 · 23.52 Impact Factor
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