2. Academic Validation
  3. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

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

  • J Med Chem. 2008 Jan 24;51(2):196-218. doi: 10.1021/jm701018h.
Paul A Brough 1,  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 James,  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
Affiliations

Affiliation

  • 1 Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K. p.brough@ vernalis.com
PMID: 18020435 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 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%.

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