Document Detail

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.
MedLine Citation:
PMID:  19610616     Owner:  NLM     Status:  MEDLINE    
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.
Paul A Brough; Xavier Barril; Jenifer Borgognoni; Patrick Chene; Nicholas G M Davies; Ben Davis; Martin J Drysdale; Brian Dymock; Suzanne A Eccles; Carlos Garcia-Echeverria; Christophe Fromont; Angela Hayes; Roderick E Hubbard; Allan M Jordan; Michael Rugaard Jensen; Andrew Massey; Angela Merrett; Antony Padfield; Rachel Parsons; Thomas Radimerski; Florence I Raynaud; Alan Robertson; Stephen D Roughley; Joseph Schoepfer; Heather Simmonite; Swee Y Sharp; Allan Surgenor; Melanie Valenti; Steven Walls; Paul Webb; Mike Wood; Paul Workman; Lisa Wright
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-09-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4794-809     Citation Subset:  IM    
Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, UK.
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MeSH Terms
Administration, Oral
Antineoplastic Agents / chemical synthesis*,  pharmacology
Binding, Competitive
Crystallography, X-Ray
Fluorescence Polarization
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Mice, Inbred BALB C
Pyrimidines / chemical synthesis*,  pharmacology
Xenograft Model Antitumor Assays
Grant Support
C309/A8274//Cancer Research UK; CA309/A2187//Cancer Research UK
Reg. No./Substance:
0/Antineoplastic Agents; 0/HSP90 Heat-Shock Proteins; 0/Pyrimidines

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