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]
NSC319726 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Glioblastoma-patient-derived cells
12 pM to 25 nM
48 hours
NSC319726 induces oxidative stress and cell cycle arrest by binding copper
Cell Chem Biol. 2018 May 17;25(5):585-594.e7.
MEF p53R172H/R172H
1 µM
24 hours
evaluates the growth inhibitory effect of NSC319726 on mouse p53R172H mutant cells
Cancer Cell. 2012 May 15;21(5):614-625.
SKOV3 (p53−/−)
1 µM
24 hours
evaluates the growth inhibitory effect of NSC319726 on p53 null cells
Cancer Cell. 2012 May 15;21(5):614-625.
OVCAR3 (p53R248W)
1 µM
24 hours
evaluates the growth inhibitory effect of NSC319726 on p53R248W mutant cells
Cancer Cell. 2012 May 15;21(5):614-625.
TOV112D (p53R175H)
1 µM
24 hours
induces a WT-like conformational change in the p53R175H mutant protein and apoptosis
Cancer Cell. 2012 May 15;21(5):614-625.
TOV112D
1 μM
72 hours
Evaluate the synergy of ZMC1 with cytotoxic chemotherapy or radiation, results showed that ZMC1 alone was effective but did not show synergy when combined with chemotherapy or radiation.
Mol Cancer Ther. 2019 Aug;18(8):1355-1365.
Escherichia coli
10 μg/mL
16-20 hours
To evaluate the antimicrobial activity of NSC319726 against E. coli AHDRCC 81113, showing an IC50 of 5.432 ± 2.731 μg/mL (0.0232 ± 0.012 μM).
Biomolecules. 2018 Dec 7;8(4):166.
TOV112D cells
1 μM
4 hours
Monitor ZMC1-induced refolding of p53 mutants
Elife. 2020 Dec 2;9:e61487.
H1299 cells
0.002 μM – 0.005 μM
Test the cell-killing effect of ZMC1 on p53 mutants
Evaluates the toxicity and therapeutic effect of NSC319726 on p53R172H mutant mice, showing p53R172H/R172H mice are more sensitive to NSC319726
Cancer Cell. 2012 May 15;21(5):614-625.
Nude mice NCR nu/nu
TOV112D xenograft model
Intraperitoneal injection
2.5 mg/kg
Daily for 17 days
Evaluate the in vivo synergy of ZMC1 with Nutlin 3a or ABT-199, results showed that ZMC1 combined with Nutlin 3a or ABT-199 significantly inhibited tumor growth.
Mol Cancer Ther. 2019 Aug;18(8):1355-1365.
Nude mice
Xenograft tumor model
Intraperitoneal injection
5 mg/kg
Daily
Test the efficacy of ZMC1 on p53 stability mutants in vivo
Elife. 2020 Dec 2;9:e61487.
Galleria mellonella larvae
C. auris infection model
Injection
6 and 12 mg/kg
Single dose, observed for 72 hours
Evaluation of the efficacy of NSC319726 in an invertebrate infection model, showing significantly improved survival rates compared to the untreated group
Microbiol Spectr. 2021 Dec 22;9(3):e0139521
ICR mice
Male reproductive system injury model
Intraperitoneal injection
1 mg/kg
Once daily for 5 weeks
To evaluate the toxicity of NSC319726 on the male reproductive system, results showed that NSC319726 caused testis index reduction, decreased sperm count, increased sperm malformation rate, structural damage in the testis and epididymis, impaired blood-testis barrier integrity, and decreased testosterone levels.
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