Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency.

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

Index: J. Med. Chem. 53 , 5942-55, (2010)

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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 1,000,000-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.