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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

2009; American Chemical Society; Volume: 52; Issue: 15 Linguagem: Inglês

10.1021/jm900357y

1520-4804

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,

Protein Structure and Dynamics

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.