Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency.
|
| 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.
|
|---|---|
| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 16 Pg. 5942-55 (Aug 26 2010) ISSN: 1520-4804 [Electronic] United States |
| PMID | 20718493 (Publication Type: Journal Article) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!