Small library including different phenolic compounds, such as flavonoids, tannins and coumarins. Among the different flavonoids and tannins that were able to bind Hsp90, we focused on the ellagitannin geraniin, the main polyphenolic compound in Geranium thunbergii, a medicinal plant used to treat diarrhea in Japan. Ellagitannins belong to the hydrolyzable tannin group and occur in several food plants, such as raspberries, strawberries, blackberries, pomegranate, almonds, and walnuts. In vitro and in vivo studies have demonstrated various biological activities of this class of compounds, including antioxidant, antiviral, antimutagenic, antimicrobial, and antitumor effects, suggesting that the consumption of ellagitannins might be beneficial to human health. Geraniin is a typical ellagitannin because it is composed entirely of common acyl units, such as galloyl, hexahydroxydiphenoyl, and dehydrohexahy droxydiphenoyl groups. Although variousstudies of geraniin have proved its antioxidant, antitumor, and antivirus properties, its mechanism of action is still poorly characterized. Herein, we report the results of a panel of chemical and biological approaches that demonstrate that geraniin binds to Hsp90a and inhibits its ATPase activity, thus compromising the stability of some oncogenic client proteins. Our results Z-VAD-FMK indicated that geraniin could represent an innovative scaffold for the design of new Hsp90 inhibitors SP600125 interacting with its ATPase domain. Inhibition of HSP90 has received significant attention in cancer research due to its ability to retard or block tumor growth. In this respect, Hsp90 plays a critical role in the maintenance of multiple oncogenic pathways and is required to maintain the folding, stability and functionally active conformation of many aberrant oncoproteins. In healthy cells, Hsp90 is involved in dynamic, low-affinity interactions with a plethora of proteins during folding and maturation; however, in tumor cells, it assists folding of dysregulated oncoproteins and sustains their aberrant activity. Given the diversity of the Hsp90 client proteins involved in critical cellular pathways and processes, inhibition of Hsp90 was predicted to have efficacy in a broad variety of human tumors. However, although several Hsp90 inhibitors have thus far entered into clinical trials, the development of Hsp90 inhibitors has encountered difficulties, including drug solubility and hepatic toxicity. Based on the notion that natural products are compounds pre2optimized by evolution to act against specific biological targets, we performed a structure2based screening of different plant2derived polyphenols to identify new potential Hsp90 inhibitors. By SPR 
analysis, the tannin geraniin was identified as an efficient ligand of Hsp90a, showing a high affinity for this chaperone, similar to that found for 17-AAG and derivates. The comparison of the HSP90a proteolytic patterns in the presence or absence of geraniin indicated that this compound binds at the Nterminus of the chaperone, as reported for several Hsp90 inhibitors. Through targeting the ATP-binding site of the N-terminal domain, the inhibitors probably prevent Hsp90 from forming a closed N-terminal dimeric state and, consequently, alter the chaperone activity of the molecule. This mechanism was proved for geraniin, which was able to reduce Hsp90 chaperone activity more efficiently than 17-AAG. The impaired ATPase and chaperone activities of Hsp90, caused by geraniin binding, induce cytotoxic effects in the tumor cell lines tested, with a large percentage of cells containing hypodiploid DNA. These results are in agreement with those reported in human melanoma cells, the activation of caspase-8, the cleavage of Bid, and the induction of cytochrome.