Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development

被引：222

作者：

Sun, Daqing ^{[1
]}

Li, Zhihong ^{[1
]}

Rew, Yosup ^{[1
]}

Gribble, Michael ^{[1
]}

Bartberger, Michael D. ^{[4
]}

Beck, Hilary P. ^{[1
]}

Canon, Jude ^{[5
]}

Chen, Ada ^{[1
]}

Chen, Xiaoqi ^{[1
]}

Chow, David ^{[1
]}

Deignan, Jeffrey ^{[1
]}

Duquette, Jason ^{[1
]}

Eksterowicz, John ^{[1
]}

Fisher, Benjamin ^{[1
]}

Fox, Brian M. ^{[1
]}

Fu, Jiasheng ^{[1
]}

Gonzalez, Ana Z. ^{[1
]}

De Turiso, Felix Gonzalez-Lopez ^{[1
]}

Houze, Jonathan B. ^{[1
]}

Huang, Xin ^{[6
]}

Jiang, Min ^{[3
]}

Jin, Lixia ^{[3
]}

Kayser, Frank ^{[1
]}

Liu, Jiwen ^{[1
]}

Lo, Mei-Chu ^{[1
]}

Long, Alexander M. ^{[6
]}

Lucas, Brian ^{[1
]}

McGee, Lawrence R. ^{[1
]}

McIntosh, Joel ^{[1
]}

Mihalic, Jeff ^{[1
]}

Oliner, Jonathan D. ^{[5
]}

Osgood, Tao ^{[5
]}

Peterson, Matthew L. ^{[7
]}

Roveto, Philip ^{[1
]}

Saiki, Anne Y. ^{[5
]}

Shaffer, Paul ^{[6
]}

Toteva, Maria ^{[2
]}

Wang, Yingcai ^{[1
]}

Wang, Yu Chung ^{[5
]}

Wortman, Sarah ^{[2
]}

Yakowec, Peter ^{[6
]}

Yan, Xuelei ^{[1
]}

Ye, Qiuping ^{[3
]}

Yu, Dongyin ^{[5
]}

Yu, Ming ^{[1
]}

Zhao, Xiaoning ^{[1
]}

Zhou, Jing ^{[1
]}

Zhu, Jiang ^{[1
]}

Olson, Steven H. ^{[1
]}

Medina, Julio C. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery, 1120 Vet Blvd, San Francisco, CA 94080 USA

[2] Amgen Inc, Dept Pharmaceut, San Francisco, CA 94080 USA

[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA 94080 USA

[4] Amgen Inc, Dept Therapeut Discovery, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Oncol Res, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Dept Therapeut Discovery, Cambridge, MA 02142 USA

[7] Amgen Inc, Dept Pharmaceut, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 04期

关键词：

PROTEIN-PROTEIN INTERACTION; SMALL-MOLECULE ANTAGONISTS; STRUCTURE-BASED DESIGN; P53-MDM2; INTERACTION; CANCER-THERAPY; P53; PATHWAY; ACTIVATION; APOPTOSIS;

D O I：

10.1021/jm401753e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR K-D = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

引用

页码：1454 / 1472

页数：19

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