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Hsp90 has emerged as an important anticancer drug target because of its essential role in promoting the folding and maturation of many oncogenic proteins. The authors describe the development of the first high-throughput screen, based on AlphaScreen technology, to identify a novel type of Hsp90 inhibitors that interrupt its interaction with the cochaperone HOP. The assay used the 20-mer C-terminal peptide of Hsp90 and the TPR2A domain of HOP. Assay specificity was demonstrated by measuring different interactions using synthetic peptides, with measured IC50s in good agreement with reported values. The assay was stable over 12 h and tolerated DMSO up to 5%. The authors first validated the assay by screening against 20,000 compounds in a 384-well format. After further optimization into a 1536-well format, it was screened against an NIH Chemical Genomics Center library of 76,134 compounds, with a signal-to-background ratio of 78 and Z' factor of 0.77. The present assay can be used for discovery of novel small-molecule Hsp90 inhibitors that can be used as chemical probes to investigate the role of cochaperones in Hsp90 function. Such molecules have the potential to be developed into novel anticancer drugs, for use alone or in combination with other Hsp90 inhibitors.

An AlphaScreen™-Based High-Throughput Screen to Identify Inhibitors of Hsp90-Cochaperone Interaction