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

FEDERICCI F, CAMISAY MF, DE LEO S, GALIGNIANA MD, MAZAIRA G

Mar del Plata

Congreso; LXI Reunión Anual de SAIC; 2016

The activity and stability of several oncoproteins require the molecular chaperon Hsp90 action. The tumoral cells are consider addicts to the action of Hsp90, because they avoid the degradation of the client proteins preventing triggering mechanisms that promote cell death. Thus they result essential in the maintenance of cellular proteostasis and cell survival. The inhibition of Hsp90 ATPase activity shows strong antitumoral effects and seems to be the only chemotherapeutics agents capable of simultaneasly affects the biggest hallmarks of cancer. However, side effects remain a concern. We studied some new compounds as potential therapeutic agents. Those were designed by molecular docking and synthesized from resorcinol or Schiff bases of 2,4-dihydroxy benzaldehyde and 5-chloro-2,4-dihydroxy benzaldehyde derivatives. Previous studies suggest that these structures could improve the interaction with the target and reduce the toxic effects. Consequently the effect on Hsp90 ATPase activity in vitro, the viability of prostate cancer cell models and translocation of steroids receptors relevant to the development and progression of such pathology was assessed. Geldanamycin (GA), a known inhibitor of Hsp90, was used as a positive control in all tests. The results confirm the predictions of docking methods and show that the compounds are capable of inhibiting Hsp90 ATPase activity. In contrast to the effect of GA, the import of steroid receptors was unaffected by synthetic drugs. However, S49, S50, S52, S56, S57, S58, S60 and S61 compounds have an inhibitory effect on the viability of PC3 cells, although its inhibitory potency is less than that of GA. With the aim of a possible clinical use of effects such dissociation may be desirable. The most significant results were the S 57 and S58, which effects on cell viability are close to those of GA. Our study describes the effect of new inhibitors Hsp90 on tumor cell viability and provides elements to modify molecules so that they are more active.