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

• Published in: Journal of medicinal chemistry Vol. 53; no. 16; pp. 5942 - 5955
• Main Authors: Murray, Christopher W, Carr, Maria G, Callaghan, Owen, Chessari, Gianni, Congreve, Miles, Cowan, Suzanna, Coyle, Joseph E, Downham, Robert, Figueroa, Eva, Frederickson, Martyn, Graham, Brent, McMenamin, Rachel, O’Brien, M. Alistair, Patel, Sahil, Phillips, Theresa R, Williams, Glyn, Woodhead, Andrew J, Woolford, Alison J.-A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.08.2010; Amer Chemical Soc
• Subjects: Aminopyridines - chemical synthesis; Aminopyridines - chemistry; Antineoplastic Agents - chemistry; Chemistry, Medicinal; Crystallography, X-Ray; Databases, Factual; Drug Design; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; Life Sciences & Biomedicine; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Pharmacology & Pharmacy; Phenols - chemical synthesis; Phenols - chemistry; Protein Binding; Protein Structure, Tertiary; Resorcinols - chemical synthesis; Resorcinols - chemistry; Science & Technology; Structure-Activity Relationship; POTENT; DESIGN; RECOGNITION; TUMOR SELECTIVITY; SHOCK-PROTEIN 90; CRYSTAL-STRUCTURE; BINDING-AFFINITY; CHAPERONE; IDENTIFICATION; SMALL-MOLECULE INHIBITOR
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100059d

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.