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|Ref Type||Journal Article|
|Authors||Yu X, Vazquez A, Levine AJ, Carpizo DR|
|Title||Allele-specific p53 mutant reactivation.|
|Date||2012 May 15|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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 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 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 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 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 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|