NOVEL HSP90-PHARMACOLOGICAL INHIBITORS IN PROSTATE CANCER

FEDERICCI F.; CAMISAY M.F.; DE LEO S.A.; ERLEJMAN A.G.; GALIGNIANA M.D.; MAZAIRA G.I.

CABA

Congreso; LXII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC) en el marco de la Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argenitna de Investigación Clínica

The heat shock protein of 90 KDa (Hsp90) is known to be associated with many of so named hallmarks of cancer. Hsp90 is the major soluble protein of the cell and interacts with nearly 10% of the eukaryotic genome, acting as a heterocomplex. This molecular chaperone is related to the activity and stability of many oncoproteins,thus tumor cells evade death programs. Tumor cells are thought to be ?addicted? to Hsp90 and the inhibition of the chaperone ATPase activity shows strong antitumor effects. Consequently, Hsp90 inhibitors seem to be interesting chemotherapeutic agents. However,side effects are still an important concern. Geldanamicyn, a known Hsp90 ATPase inhibitor, has shown concerning side effects such as nephrotoxicity and hepatotoxicity. Previous studies exhibit that some Schiff bases like imines and azometines showed cytotoxicproperties on tumor cells, and some showed only a moderated effect on the Hsp90 ATPase activity. In this work, we studied novel drugs designed 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 inhibitory action on GR and AR nuclear translocation were assessed. Geldanamycin (GA) was always used as a control of all tests. A total of 20 drugs were tested (named as 4a to 5j) and although the effectson the ATPase activity of the drugs were similar to those observed for GA, as the in silico analysis predicted; the effects on cell viability showed no relation with the drug ATPase inhibitory capability. Thisfinding support our previous works that hypothesized that the Hsp90 ATPase activity is not completely correlated with its biological activity. The study here presented provides novel insights to design more active and less toxic drugs with promising future perspectives.