4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer
| Autor: | Karen James, Ian Collins, Kathy Boxall, Brian Dymock, Paul Workman, Florence I. Raynaud, Chrisostomos Prodromou, Angela Hayes, Suzanne A. Eccles, Kwai-Ming J. Cheung, Allan E. Surgenor, Paul Webb, Martin J. Drysdale, D. Lee Walmsley, Stuart C. Ray, Allan M. Jordan, Jenifer Borgognoni, Vanessa Martins, Swee Y. Sharp, Andrea M. Lockie, Nicholas G. M. Davies, R. Howes, Lisa Wright, Thomas P. Matthews, Andrew Massey, Michael Wood, Roderick E. Hubbard, Wynne Aherne, Stephen D. Roughley, Alexandra Fink, Harry Finch, Julie E. Cansfield, Christopher J. Northfield, Paul Brough, Edward McDonald, Xavier Barril, Laurence H. Pearl |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Transplantation Heterologous Mice Nude Antineoplastic Agents Fluorescence Polarization Crystallography X-Ray Binding Competitive Mice Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery Animals Humans Structure–activity relationship HSP90 Heat-Shock Proteins Cell Proliferation biology Cell growth Chemistry Ligand binding assay Isoxazoles Resorcinols Hsp90 In vitro Transplantation Biochemistry Cancer research biology.protein Molecular Medicine Drug Screening Assays Antitumor Signal transduction Neoplasm Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 51:196-218 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm701018h |
| Popis: | 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 approximately 50%. |
| Databáze: | OpenAIRE |
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