Assay design and development strategies for finding Hsp90 inhibitors and their role in human diseases.

Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the maturation of its client proteins including protein kinases, transcription factors, and steroid hormone receptors which are structurally and functionally diverse. These client proteins are involved in various cellular signaling pathways, and Hsp90 is implicated in various human diseases including cancer, inflammation, and diseases associated with protein misfolding; thus making Hsp90 a promising target for drug discovery. Some of its client proteins are well-known cancer targets. Instead of targeting these client proteins individually, however, targeting Hsp90 is more practical for cancer drug development. Efforts have been invested in recognizing potential drugs for clinical use that inhibit Hsp90 activity and result in the prevention of Hsp90 client maturation and dampening of subsequent signaling cascades. Here, we discuss current assays and technologies used to find and characterize Hsp90 inhibitors that include biophysical, biochemical, cell-based assays and computational modeling. This review highlights recent discoveries that N-terminal isoform-selective compounds and inhibitors that target the Hsp90 C-terminus that may offer the potential to overcome some of the detriments observed with pan Hsp90 inhibitors. The tools and assays summarized in this review should be used to develop Hsp90-targeting drugs with high specificity, potency, and drug-like properties that may prove immensely useful in the clinic.