EFFECT OF NOVEL INHIBITORS ON THE BIOLOGICAL ACTIVITY OF HSP90 IN PROSTATE CANCER

SOL CIUCCI, FERNANDO FEDERICCI, GABRIEL GARCÍA, MARÍA FERNANDA CAMISAY, SONIA DE LEO, ALEJANDRA ERLEJMAN, MARIO GALIGNIANA, GISELA MAZAIRA.

Congreso; LXIII Reunión Anual de SAIC; 2018

SAIC

Hsp90 is a molecular chaperone that stabilizes in an ATP-dependent manner, the active conformation of a large number of proteins with stable tertiary structure. Several substrate proteins of this chaperone are related to tumor development and progression, hence making Hsp90 an attractive target for antitumor therapy. Inhibition of Hsp90 ATPase activity shows strong antitumor effects, and Hsp90 inhibitors seem to be the only chemotherapeutic agents capable to affect all cancer hallmarks. However, drug side effects are still an important concern. The aim of the present work was the study of novel compounds as potential antitumoral therapeutic agents. To its effect, drugs were designed and analyzed by in silico molecular docking simulations. Next, we assessed the effects of the drugs on the Hsp90 ATPase activity in vitro, viability and migration of prostate cancer cell models, and their inhibitory action on glucocorticoid receptor (GR) nuclear translocation. Geldanamycin (GA), a known Hsp90 inhibitor, was used as a positive control in all experiments. A total of 5 compounds (named N15, A15, C3, C6 and P1) were assayed. all of them confirmed in silico predictions regarding their ability to inhibit Hsp90 ATPase activity. As we expected, cell treatment with GA prevented steroid receptor nuclear import, and showed a negative effect on the viability and migration of PC3 cells. All the synthetic drugs showed an inhibitory action on cell migration, but none had effect on the GR nuclear import. Pyrazoline-derivative compounds (C3 and C6) were the only compounds that showed inhibition of cell viability. These properties could have pharmacological relevance, given the lack of side effects such as steroid receptor inhibition, which is a desirable characteristic for pharmacological applications. Moreover, the study provides novel insights that could contribute to the design of more active and less toxic drugs.