A Potent Small-Molecule Inhibitor of the MDM2-p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice

被引：245

作者：

Zhao, Yujun ^{[1
,2
,3
,4
]}

Yu, Shanghai ^{[1
,2
,3
,4
]}

Sun, Wei ^{[1
,2
,3
,4
]}

Liu, Liu ^{[1
,2
,3
,4
]}

Lu, Jianfeng ^{[1
,2
,3
,4
]}

McEachern, Donna ^{[1
,2
,3
,4
]}

Shargary, Sanjeev ^{[1
,2
,3
,4
]}

Bernard, Denzil ^{[1
,2
,3
,4
]}

Li, Xiaoqin ^{[5
]}

Zhao, Ting ^{[5
]}

Zou, Peng ^{[5
]}

Sun, Duxin ^{[5
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 13期

基金：

美国国家卫生研究院;

关键词：

STRUCTURE-BASED DESIGN; P53; ANTAGONISTS; ACTIVATION; GROWTH; CANCER; DOMAIN;

D O I：

10.1021/jm4005708

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent, MDM2 inhibitor (K-i = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, of human cancer with oral administration and represents the most potent complete, and durable tumor regression in two types xenograft models and efficacious MDM2 inhibitor reported to date.

引用

页码：5553 / 5561

页数：9

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