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RG7388

现货
Catalog No.
A3763
MDM2拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,750.00
现货
5mg
¥ 1,300.00
现货
10mg
¥ 1,800.00
现货
25mg
¥ 3,500.00
现货
50mg
¥ 4,750.00
现货

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Background

RG7388 is a second generation clinical MDM2 inhibitor with superior potency and selectivity.
It is a highly potent pyrrolidine compound. RG7388 is more potent and selective than RG7112. In human cancer cell lines, IC50 value of RG7388 in HTRF binding assays is 6 nM and IC50 value of RG7388 in MTT proliferation assays is 0.03μM. [1]
In human cancer cell lines, RG7388 blocks p53−MDM2 binding and effectively activates the p53 pathway, leading to cell cycle arrest and/or apoptosis in cell lines expressing wild-type p53 and tumor growth inhibition or regression of osteosarcoma xenografts in nude mice. RG7388 is undergoing clinical investigation in solid and hematological tumors. [1]
In rhabdomyosarcoma xenografts mice, RG7388 increased the activity of Ionizing radiation (XRT) in both rhabdomyosarcoma models and did not increasing local XRT-induced skin toxicity. Changes in TP53-responsive genes were consistent with the synergistic activity of RG7388 and XRT in the Rh18 model. [2]
RG7388 GI50 concentrations of wt p53 was a >200-fold difference versus mutant cell lines. Comparing with MYCN- cells, Tet21N MYCN+ cells were more sensitive to RG7388. In five p53-wt neuroblastoma cell lines, combining use of RG7388 with cisplatin, topotecan, doxorubicin, busulfan and temozolomide were synergistic led to increased apoptosis and higher caspase-3/7 activity. RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity. [3]
References:
1.Ding Q, Zhang Z, Liu JJ et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979-83.
2.Phelps D, Bondra K, Seum S et al. Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Pediatr Blood Cancer. 2015 Apr 1. doi: 10.1002/pbc.25465.
3.Chen L, Rousseau RF, Middleton SA et al. Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21.

文献引用

1. Stolte B, Iniguez AB, et al. "Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma." J Exp Med. 2018 Aug 6;215(8):2137-2155. PMID:30045945
2. Lu J, Guan S, et al. "Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma." Oncotarget. 2016 Dec 13;7(50):82757-82769. PMID:27764791

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt616.48
Cas No.1229705-06-9
FormulaC31H29Cl2F2N3O4
SynonymsRG 7388;RG-7388
Solubility≥30.824 mg/mL in DMSO, ≥6.96 mg/mL in EtOH with gentle warming, <2.16 mg/mL in H2O
Chemical Name4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid
SDFDownload SDF
Canonical SMILESCC(C)(C)CC1C(C(C(N1)C(=O)NC2=C(C=C(C=C2)C(=O)O)OC)C3=C(C(=CC=C3)Cl)F)(C#N)C4=C(C=C(C=C4)Cl)F
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

激酶实验 [1]:

生化结合亲和力-HTRF测定

在含50 mM Tris-HCl,pH 7.4,100 mM NaCl,1 mM DTT,0.02或0.2 mg/mL BSA的缓冲液中进行p53-MDM2 HTRF测定。将小分子抑制剂(溶于DMSO的10 mM储备溶液)等分至96深孔板中,将其置于4 ℃下储存。测定前,迅速地将其解冻并混合。在37 ℃下,将化合物与GST-MDM2和生物素化p53肽一起孵育1小时。然后加入Phycolink山羊抗GST(1型)别藻蓝蛋白和Eu-8044-链霉亲和素,在室温下,将其孵育1小时。使用Envision荧光阅读器读取96孔板的数据。通过板间重复两次或重复三次的数据确定IC50值。采用4 Parameter Logistic Model (Sigmoidal Dose-Response Model) 和方程Y = (A + ((B - A)/(1 + ((C/x)^D)))),通过XLfit4 (Microsoft)分析数据。在方程中,A和B分别代表有抑制剂或无抑制剂情况下的酶活性,C代表IC50,D代表Hill系数。

细胞实验 [1]:

细胞系

野生型 (wt)-p53肿瘤细胞系 (SJSA1, RKO, HCT116)

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

~ 10 μM;24小时

实验结果

在表达野生型p53的癌细胞中,RG7388抑制细胞增殖,其IC50值为30 nM。此外,RG7388呈剂量依赖性地诱导p53稳定化、细胞周期阻滞以及细胞凋亡。

动物实验 [1]:

动物模型

携带SJSA1人骨肉瘤异种移植物的小鼠模型

给药剂量

25或50 mg/kg;口服给药;每日1次,持续32天

实验结果

在小鼠SJSA1人骨肉瘤异种移植模型中,RG7388(25 mg/kg,口服给药)抑制肿瘤生长并使其消退。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Ding Q, Zhang Z, Liu JJ et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979-83.

质量控制

化学结构

RG7388

相关生物数据

RG7388

相关生物数据

RG7388