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MI-1061 Sale

目录号 : GC36605

MI-1061 是一种有效的,口服可生物利用的,化学稳定性的 MDM2 (MDM2-p53 互作) 抑制剂 (IC50=4.4 nM; Ki=0.16 nM)。MI-1061 能有效激活 p53,诱导细胞凋亡,并具有抗肿瘤活性。

MI-1061 Chemical Structure

Cas No.:1410737-34-6

规格 价格 库存 购买数量
1mg
¥1,768.00
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5mg
¥3,150.00
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产品描述

MI-1061 is a potent, orally bioavailable, and chemically stable MDM2 (MDM2-p53 interaction) inhibitor (IC50=4.4 nM; Ki=0.16 nM). MI-1061 potently activates p53, induces apoptosis, and has anti-tumor activity[1]. IC50: 4.4 nM (MDM2)[1]Ki: 0.16 nM (MDM2)

MI-1061 achieves IC50=100 and 250 nM in the SJSA-1 and HCT-116 p53+/+ cell lines, respectively, and has IC50>10000 nM in the p53 knockout cell line HCT-116 p53-/-cell line[1].

MI-1061 is capable of achieving tumor regression in the SJSA-1 xenograft tumor model in mice with oral administration[1].

[1]. Aguilar A, et al. Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannichring-opening-cyclization reaction mechanism in spiro-oxindoles. J Med Chem. 2014 Dec 26;57(24):10486-98.

Chemical Properties

Cas No. 1410737-34-6 SDF
Canonical SMILES O=C(O)C1=CC=C(NC([C@H](N2)[C@H](C3=CC=CC(Cl)=C3F)[C@]4(C(NC5=C4C=CC(Cl)=C5)=O)C62CCCCC6)=O)C=C1
分子式 C30H26Cl2FN3O4 分子量 582.45
溶解度 DMSO: 300 mg/mL (515.07 mM) 储存条件 Store at -20°C
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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。
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1 mg 5 mg 10 mg
1 mM 1.7169 mL 8.5844 mL 17.1689 mL
5 mM 0.3434 mL 1.7169 mL 3.4338 mL
10 mM 0.1717 mL 0.8584 mL 1.7169 mL
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Research Update

Targeted Degradation of MDM2 as a New Approach to Improve the Efficacy of MDM2-p53 Inhibitors

J Med Chem 2019 Jan 24;62(2):445-447.PMID:30575392DOI:10.1021/acs.jmedchem.8b01945.

MDM2 is a key oncogenic protein that serves as a negative regulator of the tumor suppressor p53. While a number of inhibitors of the MDM2-p53 interaction have progressed to clinical testing as treatments for a variety of hematologic and solid tumor cancers, the results thus far have been mixed, with perhaps the strongest responses observed in relapsed/refractory acute myeloid leukemia (AML). In an effort to improve the efficacy for this class of compounds, researchers have turned to targeted degradation of MDM2. IMiD-based MDM2 PROTAC 8, which potently reduces MDM2 protein levels through targeted degradation, exhibits enhanced efficacy in the RS4;11 xenograft model relative to a nondegrading MDM2-p53 inhibitor MI-1061.

Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles

J Med Chem 2014 Dec 26;57(24):10486-98.PMID:25496041DOI:10.1021/jm501541j.

Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four diastereoisomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with Ki = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice.