Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand EfficiencyClick to copy article linkArticle link copied!
- Christopher W. Murray
- Maria G. Carr
- Owen Callaghan
- Gianni Chessari
- Miles Congreve
- Suzanna Cowan
- Joseph E. Coyle
- Robert Downham
- Eva Figueroa
- Martyn Frederickson
- Brent Graham
- Rachel McMenamin
- M. Alistair O’Brien
- Sahil Patel
- Theresa R. Phillips
- Glyn Williams
- Andrew J. Woodhead
- Alison J.-A. Woolford
Abstract
Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1000000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.
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