@article {200, title = {Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone}, journal = {Journal of medicinal chemistry}, volume = {52}, year = {2009}, month = {2009/08/13/}, pages = {4794 - 4809}, 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 crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.}, keywords = {Administration, Competitive; Crystallography, Inbred BALB C; Pyrimidines/chemical synthesis/pharmacology; Xenograft Model Antitumor Assays, Oral; Animals; Antineoplastic Agents/chemical synthesis/pharmacology; Binding, X-Ray; Female; Fluorescence Polarization; HSP90 Heat-Shock Proteins/antagonists \& inhibitors; Humans; Male; Mice; Mice}, author = {Brough,P. A. and Barril, Xavier and Borgognoni,J. and Chene,P. and Davies,N. G. and Davis,B. and Drysdale,M. J. and Dymock,B. and Eccles,S. A. and Garcia-Echeverria,C. and Fromont,C. and Hayes,A. and Hubbard,R. E. and Jordan,A. M. and Jensen,M. R. and Massey,A. and Merrett,A. and Padfield,A. and Parsons,R. and Radimerski,T. and Raynaud,F. I. and Robertson,A. and Roughley,S. D. and Schoepfer,J. and Simmonite,H. and Sharp,S. Y. and Surgenor,A. and Valenti,M. and Walls,S. and Webb,P. and Wood,M. and Workman,P. and Wright,L.} }