Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges

被引：223

作者：

Wang, Shaomeng ^{[1
]}

Zhao, Yujun

Aguilar, Angelo

Bernard, Denzil

Yang, Chao-Yie

机构：

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

来源：

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE | 2017年 / 7卷 / 05期

基金：

美国国家卫生研究院;

关键词：

STRUCTURE-BASED DESIGN; P53; PATHWAY; IN-VIVO; CLINICAL DEVELOPMENT; GENE AMPLIFICATION; HIGHLY POTENT; INHIBITORS; DISCOVERY; TUMORS; ONCOPROTEIN;

D O I：

10.1101/cshperspect.a026245

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 smallmolecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.

引用

页数：10

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