NOVEL LIGANDS OF THE HSP90-ATPASE DOMAIN AND THEIR EFECTS IN A PROSTATE CANCER CELL MODEL

FERNANDO FEDERICCI; MARÍA FERNANDA CAMISAY; SONIA DE LEO; MARIO GALIGNIANA; GISELA MAZAIRA

Mar del Plata

Congreso; LXI Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC),; 2016

Sociedad Argentina de Investigación Clínica

The activity and stability of several oncoproteins depend on the molecular chaperone Hsp90. Tumor cells are thought to be ?addicted? to Hsp90, such that most of the client proteins of the chaperone evade degradation and, therefore, cells avoid the cell death program. The 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, side effects are still an important concern. Previous studies showed that both resorcinol derivatives and Schiff bases of 2,4-dihydroxy-benzaldehyde or 5-chloro-2,4-dihydroxy-benzaldehyde, show good binding capacity to the ATPase domain of Hsp90, and reduced toxic effects. Here, we analyzed novel drugs based on those chemical frames as potential therapeutic agents. First, drugs were designed and analyzed by in silico molecular docking simulations. Then, the effect on Hsp90 ATPase activity in vitro, the viability of prostate cancer cell models, and inhibitory action on GR and AR nuclear translocation were assessed. Geldanamycin (GA), a known Hsp90 inhibitor, was always used as a positive control in all tests. A total of 13 compounds (named as S49 to S61) were assayed, and most of them confirmed the in silico predictions on their ability to inhibit Hsp90 ATPase activity. While cell treatment with GA prevented steroid receptor nuclear import, the synthetic drugs were not active in this regard. Nonetheless, compounds S49, S50, S52, S56, S57, S58, S60 and S61 showed inhibitory action on the viability of PC3 cells. The most significant effects were observed for S57 and S58, whose potency on cell viability was equivalent to that measured for GA. These properties could have pharmacological relevance since the lack of side effects such as steroid receptor inhibition is desirable. Moreover, the study provides novel insights to design more active and less toxic drugs