Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno [2, 3-d] pyrimidine inhibitors of the Hsp90 molecular …

…, C Garcia-Echeverria, C Fromont…

Index: Brough, Paul A.; Barril, Xavier; Borgognoni, Jenifer; Chene, Patrick; Davies, Nicholas G. M.; Davis, Ben; Drysdale, Martin J.; Dymock, Brian; Eccles, Suzanne A.; Garcia-Echeverria, Carlos; Fromont, Christophe; Hayes, Angela; Hubbard, Roderick E.; Jordan, Allan M.; Jensen, Michael Rugaard; Massey, Andrew; Merrett, Angela; Padfield, Antony; Parsons, Rachel; Radimerski, Thomas; Raynaud, Florence I.; Robertson, Alan; Roughley, Stephen D.; Schoepfer, Joseph; Simmonite, Heather; Sharp, Swee Y.; Surgenor, Allan; Valenti, Melanie; Walls, Steven; Webb, Paul; Wood, Mike; Workman, Paul; Wright, Lisa Journal of Medicinal Chemistry, 2009 , vol. 52, # 15 p. 4794 - 4809

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Citation Number: 111

Abstract

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2- aminothieno [2, 3-d] pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein ...