4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

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• 作者：Paul A. Brough ; Wynne Aherne ; Xavier Barril ; Jenifer Borgognoni ; Kathy Boxall ; Julie E. Cansfield ; Kwai-Ming J. Cheung ; Ian Collins ; Nicholas G. M. Davies ; Martin J. Drysdale ; Brian Dymock ; Suzanne A.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 24, 2008
• 年：2008
• 卷：51
• 期：2
• 页码：196 - 218
• 全文大小：1104K
• 年卷期：v.51,no.2(January 24, 2008)
• ISSN：1520-4804

文摘

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 GI₅₀ 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 ~50%.