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Ref Type Journal Article
PMID (22624712)
Authors Yu X, Vazquez A, Levine AJ, Carpizo DR
Title Allele-specific p53 mutant reactivation.
Journal Cancer cell
Vol 21
Issue 5
Date 2012 May 15
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
NSC319726 NSC319726 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NSC319726 NSC-319726|NSC 319726 p53 Activator 11 NSC319726 restores wild-type conformation to mutant Tp53, resulting in reactivation of Tp53 signaling in Tp53-mutant cells, and potentially leading to increased tumor cell death (PMID: 22624712, PMID: 26719703).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 R175H breast cancer sensitive NSC319726 Preclinical - Cell culture Actionable In a preclinical study, breast cancer cells harboring TP53 R175H demonstrated increased sensitivity to NSC319726 in culture (PMID: 22624712). 22624712
TP53 wild-type lung large cell carcinoma resistant NSC319726 Preclinical - Cell line xenograft Actionable In a preclinical study, NSC319726 did not inhibit tumor growth in xenograft models of TP53 wild-type lung large cell carcinoma (PMID: 22624712). 22624712
TP53 R175L lung large cell carcinoma sensitive NSC319726 Preclinical - Cell culture Actionable In a preclinical study, lung large cell carcinoma cells harboring TP53 R175L demonstrated increased sensitivity to NSC319726 in culture (PMID: 22624712). 22624712
TP53 R175H ovarian cancer sensitive NSC319726 Preclinical - Cell culture Actionable In a preclinical study, ovarian cancer cells harboring TP53 R175H demonstrated increased sensitivity to NSC319726-induced growth inhibition in culture and in cell line xenograft models (PMID: 22624712). 22624712
TP53 R273W breast cancer resistant NSC319726 Preclinical - Cell culture Actionable In a preclinical study, NSC319726 did not inhibit tumor growth in xenograft models of breast cancer harboring TP53 R273W (PMID: 22624712). 22624712