Targeting conserved water molecules: design of 4-aryl-5-cyanopyrrolo [2, 3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based …

…, MJ Drysdale, N Foloppe, S Geoffrey, B Gibbons…

Index: Davies, Nicholas G.M.; Browne, Helen; Davis, Ben; Drysdale, Martin J.; Foloppe, Nicolas; Geoffrey, Stephanie; Gibbons, Ben; Hart, Terance; Hubbard, Roderick; Jensen, Michael Rugaard; Mansell, Howard; Massey, Andrew; Matassova, Natalia; Moore, Jonathan D.; Murray, James; Pratt, Robert; Ray, Stuart; Robertson, Alan; Roughley, Stephen D.; Schoepfer, Joseph; Scriven, Kirsten; Simmonite, Heather; Stokes, Stephen; Surgenor, Allan; Webb, Paul; Wood, Mike; Wright, Lisa; Brough, Paul Bioorganic and Medicinal Chemistry, 2012 , vol. 20, # 22 p. 6770 - 6789

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Citation Number: 13

Abstract

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo [2, 3-d] pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a ...