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A fluorescence polarization assay for inhibitors of Hsp90

Research output: Contribution to journalArticlepeer-review

  • R. Howes
  • Xavier Barril
  • Brian Dymock
  • Katherine Grant
  • C. J. Northfield
  • A. G. S. Robertson
  • Allan Surgenor
  • J. Wayne
  • Lisa Wright
  • Dr Karen E. Ball
  • Thomas P. Matthews
  • K.-M. Cheung
  • E. MacDonald
  • Paul Workman
  • Martin J. Drysdale
Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a Xuorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect aYnity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors.
Original languageEnglish
Pages (from-to)202-213
JournalAnalytical Biochemistry
Issue number2
Early online date23 Jan 2006
Publication statusPublished - 15 Mar 2006

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