NSC319726 is a mutant p53R175 reactivator inhibiting growth of fibroblasts expressing the p53R175 mutation (IC50 = 8 nM) and showing no inhibition forp53 wild-type cells.
NSC319726 is a p53R175 mutant reactivator, which can restores WT structure and function to the p53R175 mutant. Cell lines with p53R175 mutant, including MEF cell lines from p53R172H/R172H mice, HOP92 (R175L), TOV112D (R175H), AU565 (R175H), SK-BR-3 (R175H), exhibited more sensitivity to cell lines with p53 WT, p53R248, or p53R273. NSC319726 could induce a ‘‘WT-like’’ conformational change in the p53-175 mutant protein and reactivate its function as p53 WT, as treatment with 1μM NSC319726 led a significant decrease of p53 protein level in TOV112D cells
(R175 mutant) within 8h and restored p53 protein level to normal level at 12h later, which can be eliminated by Mdm2 antagonist Nutlin-3. Administration of NSC319726 at dose of 5 or 10mg/kg, i.p., for 7 days, selectively killed p53R172H knockin mice with extensive apoptosis. Daily intravenous administration of NSC319726 at 1 or 0.1mg/kg selectively inhibited xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner.
作用机制
NSC319726 induced a ‘‘WT-like’’ conformational change in the p53-175 mutant protein. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes.[1]
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