CONICET | Buscador de Institutos y Recursos Humanos

The heat shock protein of 90 KDa (Hsp90) is known to be associatedwith many of so named hallmarks of cancer. Hsp90 is the majorsoluble protein of the cell and interacts with nearly 10% of the eukaryoticgenome, acting as a heterocomplex. This molecular chaperoneis related to the activity and stability of many oncoproteins,thus tumor cells evade death programs. Tumor cells are thought tobe ?addicted? to Hsp90 and the inhibition of the chaperone ATPaseactivity shows strong antitumor effects. Consequently, Hsp90 inhibitorsseem to be interesting chemotherapeutic agents. However,side effects are still an important concern. Geldanamicyn, a knownHsp90 ATPase inhibitor, has shown concerning side effects suchas nephrotoxicity and hepatotoxicity. Previous studies exhibit thatsome Schiff bases like imines and azometines showed cytotoxicproperties on tumor cells, and some showed only a moderated effecton the Hsp90 ATPase activity. In this work, we studied novel drugsdesigned and analyzed by in silico molecular docking simulations.Then, the effects on the ATPase activity of in vitro Hsp90 was studiedand with these results viability of prostate cancer cells, and inhibitoryaction on GR and AR nuclear translocation were assessed.Geldanamycin (GA) was always used as a control of all tests. A totalof 20 drugs were tested (named as 4a to 5j) and although the effectson the ATPase activity of the drugs were similar to those observedfor GA, as the in silico analysis predicted; the effects on cell viabilityshowed no relation with the drug ATPase inhibitory capability. This finding support our previous works that hypothesized that the Hsp90ATPase activity is not completely correlated with its biological activity.The study here presented provides novel insights to design moreactive and less toxic drugs with promising future perspectives.