Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 26, 2010
• 年：2010
• 卷：53
• 期：16
• 页码：5942-5955
• 全文大小：1211K
• 年卷期：v.53,no.16(August 26, 2010)
• ISSN：1520-4804

文摘

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.