Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

被引：594

作者：

Shangary, Sanjeev ^{[1
,2
]}

Qin, Dongguang ^{[1
,2
]}

McEachern, Donna ^{[1
,2
]}

Liu, Meilan ^{[1
,2
]}

Miller, Rebecca S. ^{[1
,2
]}

Qiu, Su ^{[1
,2
]}

Nikolovska-Coleska, Zaneta ^{[1
,2
]}

Ding, Ke ^{[1
,2
]}

Wang, Guoping ^{[1
,2
]}

Chen, Jianyong ^{[1
,2
]}

Bernard, Denzil ^{[1
,2
]}

Zhang, Jian ^{[1
,2
]}

Lu, Yipin ^{[1
,2
]}

Gu, Qingyang ^{[3
]}

Shah, Rajal B. ^{[4
,5
]}

Pienta, Kenneth J. ^{[1
,2
,5
]}

Ling, Xiaolan ^{[7
]}

Kang, Sanmao ^{[7
]}

Guo, Ming ^{[7
]}

Sun, Yi ^{[3
]}

Yang, Dajun ^{[7
]}

Wang, Shaomeng ^{[1
,2
,6
]}

机构：

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

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

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

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

[5] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Dept Pharmacol & Med Chem, Ann Arbor, MI 48109 USA

[7] Ascenta Therapeut Inc, Malvern, PA 19355 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 10期

关键词：

cancer therapy; MDM2-p53 protein-protein interaction; selective toxicity to tumors; small-molecule inhibitor;

D O I：

10.1073/pnas.0708917105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K-i value of 5 nM and is 10,000-fold selective for MDM2 over MDMX It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.

引用

页码：3933 / 3938

页数：6

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