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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

Posted June 8th, 2010 by pschmidtke
TitleCombining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone
Publication TypeJournal Article
Year of Publication2009
AuthorsBrough, PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L
JournalJournal of medicinal chemistry
Volume52
Issue15
Pagination4794 - 4809
Date Published2009/08/13/
KeywordsAdministration, 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
AbstractInhibitors 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.