Nutlin-3 化学構造
分子量: 581.5

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Quality Control & MSDS

製品説明

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    Mdm2製品生物活性の比較
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製品の説明

生物活性

製品説明 Nutlin-3は、強力で選択的なMDM-2拮抗剤で、IC50 が 90 nMです。Mdm2は、それ自体とp53のためのRING指依存的なユビキチン・タンパク質リガーゼです。
ターゲット Mdm2
IC50 90 nM [1]
In vitro試験 Nutlin-3 potently inhibits the MDM2-p53 interaction, leading to the activation of the p53 pathway. Nutlin-3 treatment induces the expression of MDM2 and p21, and displays potent antiproliferative activity with IC50 of ~1.5 μM, only in cells with wild-type p53 such as HCT116, RKO and SJSA-1, but not in the mutant p53 cell lines SW480 and MDA-MB-435. In SJSA-1 cells, Nutlin-3 treatment at 10 μM for 48 hours significantly induces caspase-dependent cell apoptosis by ~45%. Although Nutlin-3 also inhibits the growth and viability of human skin (1043SK) and mouse embryo (NIH/3T3) with IC50 of 2.2 μM and 1.3 μM, respectively, cells remain viable 1 week post-treatment even at 10 μM of Nutlin-3, in contrast with the SJSA-1 cells with viability lost at 3 μM of Nutlin-3 treatment. [1] Nutlin-3 does not induce the phosphorylation of p53 on key serine residues and reveals no difference in their sequence-specific DNA binding and ability to transactivate p53 target genes compared with phosphorylated p53 induced by the genotoxic drugs doxorubicin and etoposide, demonstrating that phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis. [2] Although binding less efficiently to MDMX than to MDM2, Nutlin-3 can block the MDMX–p53 interaction and induce the p53 pathway in retinoblastoma cells (Weri1) with IC50 of 0.7 μM. [3] Nutlin-3 at 30 μM also disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73, leading to the dose-dependent cell growth inhibition and apoptosis induction in cells without wild-type p53. [4]
In vivo試験 Oral administration of Nutlin-3 at 200 mg/kg twice daily for 3 weeks significantly inhibits the tumor growth of SJAS-1 xenografts by 90%, comparable with the effect of doxorubicin treatment with 81% inhibition of tumor growth. [1]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Biacore study Competition assay is performed on a Biacore S51. A Series S Sensor chip CM5 is utilized for the immobilization of a PentaHis antibody for capture of the His-tagged p53. The level of capture is ~200 response units (1 response unit corresponds to 1 pg of protein per mm2). The concentration of MDM2 protein is kept constant at 300 nM. Nutlin-3 is dissolved in DMSO at 10 mM and further diluted to make a concentration series of Nutlin-3 in each MDM2 test sample. The assay is run at 25 °C in running buffer (10 mM Hepes, 0.15 M NaCl, 2% DMSO). MDM2-p53 binding in the presence of Nutlin-3 is calculated as a percentage of binding in the absence of Nutlin-3 and IC50 is calculate

細胞アッセイ: [1]

細胞株 HCT116, RKO, SJSA-1, SW480, and MDA-MB-435
濃度 Dissolved in DMSO, final concentrations ~ 30 μM
反応時間 8, 24, and 48 hours
実験の流れ Cells are exposed to various concentrations of Nutlin-3 for 8, 24 and 48 hours. The transcriptional levels of p21 and MDM2 genes are analyzed by real-time PCR, and protein levels by western blotting. Cell viability is measured by the MTT assay. Cell apoptosis is determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining with flow cytometry and fluorescence microscopy.

動物実験: [1]

動物モデル Athymic female nude mice (Nu/Nu-nuBR) injected subcutaneously with SJSA-1 cells
製剤 Formulated in 2% Klucel, 0.5% Tween 80
投薬量 200 mg/kg
投与方法 Orally, twice a day

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Nutlin-3 SDF
分子量 581.5
化学式

C30H30Cl2N4O4

CAS No. 890090-75-2
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 100 mg/mL (171.96 mM)
エタノール 30 mg/mL (51.59 mM)
<1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 4-(4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one

カスタマーフィードバック (3)


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Source Cell Death Dis, 2011, 2, e243. Nutlin-3 purchased from Selleck
Method Caspase-Glo 3/7 Assays
Cell Lines UKF-NB-3 cells, UKF-NB-3r cells
Concentrations 10 μM
Incubation Time
Results Investigation of caspase 3/7 activation in response to Nutlin-3 and other cytotoxic drugs revealed that apoptosis induction is reduced and delayed in UKF-NB-3rNutlin10μM cells compared with UKF-NB-3 (Figure 2).

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Source Cell death dis, 2012, 3, e294. Nutlin-3 purchased from Selleck
Method Western Blot
Cell Lines UKF-NB cells
Concentrations 10 uM
Incubation Time 24 h
Results Only one study has reported an A76T mutation that was found in benign breast tissue. Interestingly, UKF-NB-3’RITA10 uM IV cells were as sensitive to nutlin-3 treatment as parental UKF-NB-3 cells with nutlin-3 treatment resulting in the induction of p53 response gene expression in these cells.

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Rating
Source Int J Oncol, 2014, 44, 761-8. Nutlin-3 purchased from Selleck
Method Immunoprecipitation
Cell Lines Hepatoma cells
Concentrations 20 uM
Incubation Time 24 h
Results It conducted in vivo ubiquitination assays with the treatment of Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, and found that BIRC6 knockdown still facilitated the degradation of p53 by ubiquitination independent of Mdm2.

文献中の引用 (8)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
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