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

Citations Over TimeTop 10% of 2009 papers

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.

Related Papers

• → Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle(2013)127 cited
• → A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90(1999)77 cited
• → Inhibition of GR‐mediated transcription by p23 requires interaction with Hsp90(2004)46 cited
• → Evidence for chaperone heterocomplexes containing both Hsp90 and VCP(2005)16 cited
• → Structure and function of molecular chaperones: Functions of HSP90, a major stress protein(1998)