Reference Detail

Ref Type

Journal Article

PMID

(22624712)

Authors

Yu X, Vazquez A, Levine AJ, Carpizo DR

Title

Allele-specific p53 mutant reactivation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	21	5	2012 May 15	614-625	Cancer Cell

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 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 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
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 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