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
  • 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%.