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

Research output: Contribution to journalArticlepeer-review

  • 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
  • Allan M. Jordan
  • Andrea Lockie
  • Vanessa 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

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

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