title: 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: Astex Therapeutics, Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. c.murray@astex-therapeutics.com
authors: Christopher W
authors: CW
authors: Murray
authors: Maria G
authors: MG
authors: Carr
authors: Owen
authors: O
authors: Callaghan
authors: Gianni
authors: G
authors: Chessari
authors: Miles
authors: M
authors: Congreve
authors: Suzanna
authors: S
authors: Cowan
authors: Joseph E
authors: JE
authors: Coyle
authors: Robert
authors: R
authors: Downham
authors: Eva
authors: E
authors: Figueroa
authors: Martyn
authors: M
authors: Frederickson
authors: Brent
authors: B
authors: Graham
authors: Rachel
authors: R
authors: McMenamin
authors: M Alistair
authors: MA
authors: O'Brien
authors: Sahil
authors: S
authors: Patel
authors: Theresa R
authors: TR
authors: Phillips
authors: Glyn
authors: G
authors: Williams
authors: Andrew J
authors: AJ
authors: Woodhead
authors: Alison J-A
authors: AJ
authors: Woolford
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D010636:Phenols; D012118:Resorcinols