Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-<i>d</i>]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

Paul A. Brough; Xavier Barril; Jenifer Borgognoni; Patrick Chêne; Nicholas G. Davies; Ben Davis; Martin J. Drysdale; Brian Dymock; Suzanne A. Eccles; Carlos Garcı́a-Echeverrı́a; Christophe Fromont; Angela Hayes; Roderick E. Hubbard; Allan M. Jordan; Michael Rugaard Jensen; Andrew J. Massey; Angela Merrett; Antony Padfield; Rachel Parsons; Thomas Radimerski; Florence I. Raynaud; Alan Robertson; Stephen D. Roughley; Joseph Schoepfer; Heather Simmonite; Swee Y. Sharp; A.E. Surgenor; Melanie Valenti; Steven B. Walls; Paul Webb; Mike Wood; Paul Workman; Lisa Wright

doi:10.1021/jm900357y

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

In silicoChemistryPyrimidineHsp90Chaperone (clinical)Fluorescence anisotropyComputational biologyBiochemistryIC50Cancer researchIn vitroHeat shock proteinBiology

MeSH Terms

AdministrationOralAnimalsAntineoplastic AgentsBindingCompetitiveCrystallographyX-RayFemaleFluorescence PolarizationHSP90 Heat-Shock ProteinsHumansMaleMiceMiceInbred BALB CPyrimidinesXenograft Model Antitumor Assays

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Publication Info

Year: 2009
Type: article
Volume: 52
Issue: 15
Pages: 4794-4809
Citations: 173
Access: Closed

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Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-<i>d</i>]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

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APA Style

                            
                                
                                    Paul A. Brough, 
                                
                                    Xavier Barril, 
                                
                                    Jenifer Borgognoni
                                
                                et al.
                            
                            (2009). 
                            Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-<i>d</i>]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone. 
                            Journal of Medicinal Chemistry
                            , 52
                            (15)
                            , 4794-4809.
                            https://doi.org/10.1021/jm900357y
                        

Identifiers

DOI: 10.1021/jm900357y
PMID: 19610616

Data Quality

Data completeness: 81%