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RG7112

现货
Catalog No.
A3762
MDM2抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,400.00
现货
10mg
¥ 2,520.00
现货
100mg
¥ 9,500.00
现货

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Background

RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. [1]
P53 is a potent tumor suppressor that activates the transcription of a subset of genes controlling cell-cycle progression and apoptosis. MDM2 is a negative regulator of p53 that binds the transactivation domain of p53 and inhibits its ability to activate transcription. MDM2 is also an E3 ubiquitin ligase that targets p53 for proteosomal degradation. MDM2 overexpression is one of the mechanisms by which the wild type p53 function is impaired. [2]
RG7112 has been profiled extensively in many cell lines. In 15 cancer cell lines expressing wild-type p53, it shows IC50 in the range of 0.18 - 2.2 μM. However, the inhibition is much less in seven cancer cell lines with p53 mutation, IC50 5.7 - 20.3 μM. The overall selectivity is 14-fold.
In the animal models, RG7112-induced thrombocytopenia occurred rather late during the treatment period and persisted after drug discontinuation, suggesting that the drug acts on early hematopoietic progenitor cells. This is supported by the RG7112 ability to inhibit CFU-MK colonies formation by the CD34t cells in vitro. Administration of RG7112 in rats and monkeys reduces WBC counts and, to a lesser extent, hemoglobin levels. In patients treated with RG7112, neutropenia is among the serious adverse events while anemia occurred only in 2 of 20 patients. Interestingly, when tested in vitro, the same concentration of RG7112 that reduced CFU-MK colony formation do not significantly affect the formation of BFU-E and CFU-GM derived colonies.
References:

[1] Hernan Carol, C. Patrick Reynolds, Min H. Kang et al. Initial Testing of the MDM2 Inhibitor RG7112 by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2013;60:633–641
[2] Binh Vu, Peter Wovkulich, Giacomo Pizzolato et al. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med. Chem. Lett. 2013, 4, 466−469
[3] Camelia Iancu-Rubina, Goar Mosoyana, Kelli Glenn et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Experimental Hematology 2014;42:137–145

文献引用

1. Her NG, Oh JW, et al. "Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells." Cell Death Dis. 2018 Jul 18;9(8):792. PMID:30022047
2. Miyazaki M, Otomo R, et al. "The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas." Cell Death Discov. 2018 May 10;4:56. PMID:29760954
3. Chen R, Zhou J, et al. "A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors." Biochemistry. 2017 Jun 27;56(25):3273-3282. PMID:28581721
4. Makii C, Oda K, et al. "MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53." Oncotarget. 2016 Nov 15;7(46):75328-75338. PMID:27659536
5. Kwon DH, Eom GH, et al. "MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification." Nat Commun.2016 Feb 1;7:10492. PMID:26832969

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt727.78
Cas No.939981-39-2
FormulaC38H48Cl2N4O4S
SynonymsRG-7112;RG 7112
Solubility≥36.4 mg/mL in DMSO, ≥31.87 mg/mL in EtOH, <2.37 mg/mL in H2O
Chemical Name[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone
SDFDownload SDF
Canonical SMILESCCOC1=C(C=CC(=C1)C(C)(C)C)C2=NC(C(N2C(=O)N3CCN(CC3)CCCS(=O)(=O)C)(C)C4=CC=C(C=C4)Cl)(C)C5=CC=C(C=C5)Cl
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1]:

细胞系

SJSA1骨肉瘤细胞

溶解方法

在DMSO中的溶解度>10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

24 h;10 μM

应用

在培养的癌细胞中,RG7112导致p53蛋白及其转录靶点p21和MDM2的浓度依赖性积累。由于MDM2基因扩增而表达高水平MDM2蛋白的SJSA1骨肉瘤细胞中,RG7112剂量依赖地抑制细胞生长,杀死细胞。

动物实验[1]:

动物模型

雌性Balb/c裸鼠

剂量

200 mg/kg;口服给药

应用

在SJSA1异种移植模型中评估RG7112的药效学效应。为了评估RG7112在体内激活p53反应的能力,SJSA1荷瘤小鼠用单剂量的对照或50-200 mg/kg的RG7112处理4-24小时。Western blot分析显示p53蛋白及其靶点p21和 MDM2的剂量依赖性增加。在最高剂量水平(200 mg/kg)时,在给药后的4小时,p53蛋白的水平达到最高,并持续到24小时。而在较低剂量水平下,p53调制的持续时间较短。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Tovar C, Graves B, Packman K, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models[J]. Cancer research, 2013, 73(8): 2587-2597.

生物活性

描述 RG7112是第一个用于临床的MDM2小分子抑制剂。
靶点 MDM2          
IC50            

质量控制

化学结构

RG7112

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