您当前所在的位置:首页 > 产品中心 > 产品信息
Nutlin-3_分子结构_CAS_548472-68-0)
点击图片或这里关闭

Nutlin-3

产品号 S1061 公司名称 Selleck Chemicals
CAS号 548472-68-0 公司网站 http://www.selleckchem.com
分子式 C30H30Cl2N4O4 电 话 (877) 796-6397
分子量 581.4896 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72486

产品价格信息

请登录

产品别名

标题
Nutlin-3
IUPAC标准名
4-[4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-2-one
IUPAC传统名
4-[4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

产品登记号

CAS号 548472-68-0

产品性质

作用靶点 MDM2
成盐信息 Free Base
溶解度 DMSO
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description Nutlin-3 is a potent and selective Mdm2 antagonist with IC50 of 90 nM.
Targets Mdm2
IC50 90 nM [1]
In Vitro 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 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]
Clinical Trials
Features
Protocol
Kinase Assay [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 calculated.
Cell Assay [1]
Cell Lines HCT116, RKO, SJSA-1, SW480, and MDA-MB-435
Concentrations Dissolved in DMSO, final concentrations ~ 30 μM
Incubation Time 8, 24, and 48 hours
Methods 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.
Animal Study [1]
Animal Models Athymic female nude mice (Nu/Nu-nuBR) injected subcutaneously with SJSA-1 cells
Formulation Formulated in 2% Klucel, 0.5% Tween 80
Doses 200 mg/kg
Administration Orally, twice a day
References
[1] Vassilev LT, et al. Science, 2004, 303(5659), 844-848.
[2] Thompson T, et al. J Biol Chem, 2004, 279(51), 53015-53022.
[3] Laurie NA, et al. Nature, 2006, 444(7115), 61-66.
[4] Lau LM, et al. Oncogene, 2008, 27(7), 997-1003.