4,5-diarylisoxazole HSP90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer

被引：382

作者：

Brough, Paul A. ^{[1
]}

Aherne, Wynne ^{[2
]}

Barril, Xavier ^{[1
]}

Borgognoni, Jenifer ^{[1
]}

Boxall, Kathy ^{[2
]}

Cansfield, Julie E. ^{[1
]}

Cheung, Kwai-Miny J. ^{[2
]}

Collins, Ian ^{[2
]}

Davies, Nicholas G. M. ^{[1
]}

Drysdale, Martin J. ^{[1
]}

Dymock, Brian ^{[1
]}

Eccles, Suzanne A. ^{[2
]}

Finch, Harry ^{[1
]}

Fink, Alexandra ^{[1
]}

Hayes, Angela ^{[2
]}

Howes, Robert

Hubbard, Roderick E. ^{[1
]}

James, Karen ^{[2
]}

Jordan, Allan M. ^{[1
]}

Lockie, Andrea ^{[1
]}

Martins, Vanessa ^{[2
]}

Massey, Andrew ^{[1
]}

Matthews, Thomas P. ^{[2
]}

McDonald, Edward ^{[2
]}

Northfield, Christopher J. ^{[1
]}

Pearl, Laurence H. ^{[2
]}

Prodromou, Chrisostomos ^{[2
]}

Ray, Stuart ^{[1
]}

Raynaud, Florence I. ^{[2
]}

Roughley, Stephen D. ^{[1
]}

Sharp, Swee Y. ^{[2
]}

Surgenor, Allan ^{[1
]}

Walmsley, D. Lee ^{[1
]}

Webb, Paul ^{[1
]}

Wood, Mike ^{[1
]}

Workman, Paul ^{[2
]}

Wrightt, Lisa ^{[1
]}

机构：

[1] Vernalis Ltd, Cambridge CB21 6GB, England

[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 02期

关键词：

D O I：

10.1021/jm701018h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI(50) averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by similar to 50%.

引用

页码：196 / 218

页数：23

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