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

Brough, P. A. et al. (2008) 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer. Journal of Medicinal Chemistry, 51(2), pp. 196-218. (doi: 10.1021/jm701018h)

Abstract

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%.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Drysdale, Professor Martin
• Authors: Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., Collins, I., Davies, N. G. M., Drysdale, M. J., Dymock, B., Eccles, S. A., Finch, H., Fink, A., Hayes, A., Howes, R., Hubbard, R. E., James, K., Jordan, A. M., Lockie, A., Martins, V., Massey, A., Matthews, T. P., McDonald, E., Northfield, C. J., Pearl, L. H., Prodromou, C., Ray, S., Raynaud, F. I., Roughley, S. D., Sharp, S. Y., Surgenor, A., Walmsley, D. L., Webb, P., Wood, M., Workman, P., and Wright, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Published Online: 20 November 2007