BI-0252
目录号 : GC35511
BI-0252 是一种具有口服活性，选择性的 MDM2-p53 抑制剂，IC50 值为 4 nM。 BI-0252 可诱导异种移植小鼠 SJSA-1 的所有动物肿瘤消退，同时诱导肿瘤蛋白p53 (TP53) 靶基因和凋亡标志物。
Cas No.:1818291-27-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BI-0252 is an orally active, selective MDM2-p53 inhibitor with an IC50 of 4 nM. BI-0252 can induce tumor regressions in all animals of a mouse SJSA-1 xenograft, with concomitant induction of the tumor protein p53 (TP53) target genes and markers of apoptosis[1]. IC50: 4 nM (MDM2-p53)[1]
[1]. Gollner A, et al. Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction. J Med Chem. 2016 Nov 23;59(22):10147-10162.
| Cas No. | 1818291-27-8 | SDF | |
| Canonical SMILES | ClC1=C(F)C([C@@H]2[C@@]3(C(C=CC(Cl)=C4)=C4NC3=O)N(CC5CC5)[C@@H]6[C@H]2N[C@@H](C7=CC=C(C(O)=O)C=C7)C6)=CC=C1 | ||
| 分子式 | C30H26Cl2FN3O3 | 分子量 | 566.45 |
| 溶解度 | Soluble in DMSO | 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 | 1.7654 mL | 8.8269 mL | 17.6538 mL |
| 5 mM | 0.3531 mL | 1.7654 mL | 3.5308 mL |
| 10 mM | 0.1765 mL | 0.8827 mL | 1.7654 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。
Targeted Synthesis of Complex Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2-p53 Inhibitors
ChemMedChem 2019 Jan 8;14(1):88-93.PMID:30458062DOI:10.1002/cmdc.201800617.
Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96MDM2 . The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2'-pyrrolo[2,3-c]pyrrole]-2,4'-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects.
Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction
J Med Chem 2016 Nov 23;59(22):10147-10162.PMID:27775892DOI:10.1021/acs.jmedchem.6b00900.
Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).