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NSC59984

Restores the p53 signaling pathway CAS# 803647-40-7

NSC59984

Catalog No. BCC6540----Order now to get a substantial discount!

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Chemical structure

NSC59984

3D structure

Chemical Properties of NSC59984

Cas No. 803647-40-7 SDF Download SDF
PubChem ID 5356520 Appearance Powder
Formula C12H15N3O4 M.Wt 265.27
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 33.33 mg/mL (125.65 mM; Need ultrasonic)
Chemical Name (E)-1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one
SMILES CN1CCN(CC1)C(=O)C=CC2=CC=C(O2)[N+](=O)[O-]
Standard InChIKey QKTRIGNWBRHBFV-DUXPYHPUSA-N
Standard InChI InChI=1S/C12H15N3O4/c1-13-6-8-14(9-7-13)11(16)4-2-10-3-5-12(19-10)15(17)18/h2-5H,6-9H2,1H3/b4-2+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of NSC59984

DescriptionNSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. The EC50 of NSC59984 in most cancer cells is significantly lower than those of normal cells, with EC50 of 8.38 μM for p53-null HCT116 cells. IC50 value: 8.38 μM (EC50, for p53-null HCT116 cells) Target: p53 in vitro: NSC59984 specifically restores p53 pathway signaling in mutant p53-expressing human colorectal cancer cells. NSC59984 induces cell death in tumor cells but not normal cells with little or no genotoxicity. NSC59984 induces mutant p53 protein degradation through MDM2-mediated ubiquitination in cancer cells. NSC59984 restores p53 pathway signaling through activation of p73. NSC59984 induces p73-dependent cell apoptosis in cancer. in vivo: NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner.

References:
[1]. Zhang S, et al. Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer Res. 2015 Sep 15;75(18):3842-52.

NSC59984 Dilution Calculator

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Preparing Stock Solutions of NSC59984

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.7697 mL 18.8487 mL 37.6974 mL 75.3949 mL 94.2436 mL
5 mM 0.7539 mL 3.7697 mL 7.5395 mL 15.079 mL 18.8487 mL
10 mM 0.377 mL 1.8849 mL 3.7697 mL 7.5395 mL 9.4244 mL
50 mM 0.0754 mL 0.377 mL 0.7539 mL 1.5079 mL 1.8849 mL
100 mM 0.0377 mL 0.1885 mL 0.377 mL 0.7539 mL 0.9424 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on NSC59984

NSC59984 is a promising lead compound for anti-cancer therapy that acts by targeting GOF mutant p53 and stimulates p73 to restore the p53 signaling pathway. The p53 is a tumour-suppressor protein which exerts antiproliferative effects, including growth arrest and apoptosis.

In vitro: In SW480 and DLD-1 cells, NSC59984 treatment for 3 hours dose-dependently increased the mRNA levels of p21, Noxa and Puma. NSC59984 was also found to increase p53-responsive reporter activity in both SW480 in a dose-dependent manner. The EC50 values of NSC59984 against a panel of cancer cell lines were different, varying from 8.38 to 110.49 ?M. After incubation with 12 ?M NSC59984 for 8 hours, the level ofγH2AX, a marker of genotoxicity due to DNA double-strand breaks, increased in HCT116 cells. NSC59984 induced cell death in a panel of cancer cells but displayed little or no cytotoxicity towards normal cells. Noxa mRNA slightly increased in response to 25 μM of NSC59984 in HCT116 and 12 μM of NSC59984 in p53-null HCT116 cells [1].

In vivo: In nude mice bearing colon-tumor xenografts, NSC59984 (i.p. injection, 45mg/kg) did not cause an obvious change in mouse body weights and no overt toxic effects. NSC59984 treatment significantly repressed the DLD-1 xenograft tumor growth. Tumor weight measured at day 15 reduced by 34% in DLD-1 xenograft tumors. In p73 knock-down DLD-1 xenograft tumors, NSC59984 didn’t suppress tumor growth. In p73 knock-down DLD-1 xenograft tumors, NSC59984 treatment reduced tumor weight by 18% [1].

Reference:
Zhang S, Zhou L, Hong B, et al.  Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53[J]. Cancer research, 2015, 75(18): 3842-3852.

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References on NSC59984

Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.[Pubmed:26294215]

Cancer Res. 2015 Sep 15;75(18):3842-52.

The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.

Description

NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.

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