RG7388
(Synonyms: RG 7388; RG-7388; ldasanutlin; Ro 5503781) 目录号 : GC11594
An inhibitor of the MDM2-p53 interaction
Cas No.:1229705-06-9
Sample solution is provided at 25 µL, 10mM.
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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.
| Kinase experiment [1]: | |
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Biochemical binding affinity-HTRF assay |
The p53-MDM2 HTRF assay was performed in buffer containing 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM DTT, 0.02 or 0.2 mg/mL BSA. Small-molecule inhibitors were stored in aliquots as 10 mM stock solutions in DMSO at 4°C in 96-deep-well plates. It was thawed and mixed immediately prior to testing. The compound was incubated with GST-MDM2 and a biotinylated p53 peptide for one hr at 37 °C. Phycolink goat anti-GST (Type 1) allophycocyanin and Eu-8044-streptavidin were then added and followed by one hr incubation at room temperature. Plates were read using the Envision fluorescence reader. IC50 values were determined from inter-plate duplicate or triplicate sets of data. Data were analyzed by XLfit4 (Microsoft) using a 4 Parameter Logistic Model (Sigmoidal Dose-Response Model) and the equation Y = (A + ((B - A)/(1 + ((C/x)^D)))), where A and B were enzyme activity in the absence or presence of infinite inhibitor compound, respectively, C was the IC50 and D was the Hill coefficient. |
| Cell experiment [1]: | |
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Cell lines |
Wild-type (wt)-p53 cancer cell lines (SJSA1, RKO, HCT116) |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
~ 10 μM; 24 hrs |
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Applications |
In cancer cells expressing wt-p53, RG7388 inhibited cell proliferation with an IC50 value of 30 nM, and induced dose-dependent p53 stabilization, cell cycle arrest, as well as cell apoptosis. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing SJSA1 human osteosarcoma xenografts |
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Dosage form |
25 or 50 mg/kg; p.o.; q.d., for 32 days |
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Applications |
In a mouse SJSA1 human osteosarcoma xenograft model, RG7388 (25 mg/kg, p.o.) caused tumor growth inhibition and regression. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
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. |
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| Cas No. | 1229705-06-9 | SDF | |
| 别名 | RG 7388; RG-7388; ldasanutlin; Ro 5503781 | ||
| 化学名 | 4-[[(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 | ||
| Canonical SMILES | CC(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 | ||
| 分子式 | C31H29Cl2F2N3O4 | 分子量 | 616.48 |
| 溶解度 | ≥ 30.824 mg/mL in DMSO, ≥ 6.96 mg/mL in EtOH with gentle warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6221 mL | 8.1106 mL | 16.2211 mL |
| 5 mM | 0.3244 mL | 1.6221 mL | 3.2442 mL |
| 10 mM | 0.1622 mL | 0.8111 mL | 1.6221 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet