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Allele-Specific p53 Mutant Reactivation
Open accessAbstract
Summary Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using the NCI 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 knock-in 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.
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In the citing paper
“ZMC1 induces apoptosis in a p53-dependent manner in vitro and inhibits tumor growth in vivo.”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · cites this paper as [355]
In the citing paper
“Although ZMC1 targets the p53 R175H mutant, it also affects several p53 R273H and p53 R248Q mutants that lack binding affinity between p53 and DNA.355”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · cites this paper as [355]
In the citing paper
“ZMC1 helped coordinate zinc ions at appropriate sites to restore the structure and function of the R175 mutant442 and significantly inhibited tumor growth in mice carrying the R175H mutation.441”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [441]
In the citing paper
“NSC319726, also known as ZMC1, was identified from 48129 compounds.441”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [441]
In the citing paper
“In addition, ZMC1 can chelate redox-active copper,447 increase intracellular reactive oxygen levels and decrease glutathione concentrations to exert antitumor effects.441,444”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [441]
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Citations
Cites
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Targeting p53 pathways: mechanisms, structures, and advances in therapy
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Metadata
- Authors
- Yu, X., Vazquez, A., Levine, A. J., & Carpizo, D. R.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 21
- Issue
- 5
- Pages
- 614-625
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2103174054
- Cited by
- 319
- References
- 11
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 442 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Funders
- Breast Cancer Research Foundation
- Rutgers Cancer Institute of New Jersey
- National Institutes of Health (P01CA87497)
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