In recent years, molecular chaperones such as the 90 kDa heat-shock protein (Hsp90) have surfaced as promising targets for drug discovery [1
]. Their role in the folding and maturation of various client proteins, as well as the rematuration of misfolded proteins [7
], makes them potential targets for many diseases ranging from the disruption of multiple signaling pathways associated with cancer [1
] to the clearance of protein aggregates in neurodegenerative diseases [4
]. In fact, cytotoxic inhibitors of Hsp90 are the only cancer chemotherapeutic agents known to impact all six hallmarks of cancer simultaneously [6
]. As defined by Hanahan and Weinberg, this includes 1) self-sufficiency in growth signals, 2) insensitivity to antigrowth signals, 3) evasion of apoptosis, 4) limitless replicative potential, 5) sustained angiogenesis, and 6) tissue invasion/metastasis [24
]. Disruption of the Hsp90 protein folding machinery by non-cytotoxic agents promotes dissociation of heat shock factor 1 (HSF-1), which upregulates Hsp90 and facilitates the disaggregation of proteins responsible for several neurodegenerative diseases [21
Geldanamycin (GDA), a natural product isolated from the bacteria Streptomyces hygroscopicus (), was the first identified Hsp90 inhibitor. Although it showed significant anti-proliferative activity against many cancer cell lines, its dose-limiting toxicity prevented successful completion of clinical trials. Since that time, a variety of natural product inhibitors of Hsp90 have emerged. Among these are herbimycin, radicicol, novobiocin, coumermycin A1, clorobiocin, epigallocatechin gallate (EGCG), taxol, pochonin, derrubone, gedunin, and celastrol.