Orally Bioavailable Antagonists of Inhibitor of Apoptosis Proteins Based on an Azabicyclooctane Scaffold

被引：34

作者：

Cohen, Frederick ^{[1
]}

Alicke, Bruno ^{[2
]}

Elliott, Linda O. ^{[3
]}

Flygare, John A. ^{[1
]}

Goncharov, Tatiana ^{[4
]}

Keteltas, Stephen F. ^{[1
]}

Franklin, Matthew C. ^{[4
]}

Frankovitz, Stacy ^{[5
]}

Stephan, Jean-Philippe ^{[5
]}

Tsui, Vickie ^{[1
]}

Vucic, Domagoj ^{[4
]}

Wong, Harvey ^{[6
]}

Fairbrother, Wayne J. ^{[4
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biochem Pharmacol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Assay & Automat Technol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 06期

基金：

美国国家卫生研究院;

关键词：

KAPPA-B ACTIVATION; ALPHA-DEPENDENT APOPTOSIS; SMALL-MOLECULE INHIBITORS; ML-IAP; CANCER; DESIGN; POTENT; DISCOVERY; CIAP1; XIAP;

D O I：

10.1021/jm801450c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.

引用

页码：1723 / 1730

页数：8

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