4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

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. Eccles, Harry Finch, Alexandra Fink, Angela Hayes, Robert Howes, Roderick E. Hubbard, Karen E. Ball, Allan M. Jordan, Andrea LockieVanessa Martins, Andrew Massey, Thomas P. Matthews, Edward McDonald, Christopher J. Northfield, Laurence H. Pearl, Chrisostomos Prodromou, Stuart Ray, Florence I. Raynaud, Stephen D. Roughley, Swee Y. Sharp, Allan Surgenor, D. Lee Walmsley, Paul Webb, Mike Wood, Paul Workman, Lisa Wright

Research output: Contribution to journalArticlepeer-review


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%.

Original languageEnglish
Pages (from-to)196-218
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - 24 Jan 2008


  • Animals
  • Antineoplastic Agents
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Proliferation
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Fluorescence Polarization
  • HSP90 Heat-Shock Proteins
  • Humans
  • Isoxazoles
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasm Transplantation
  • Resorcinols
  • Structure-Activity Relationship
  • Transplantation, Heterologous


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