SYNTHETIC HSP90 INHIBITORS AS PROMISING PROSTATIC CANCER THERAPEUTIC AGENTS

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

Mar del Plata

Congreso; LXIII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

According to current bibliography, the biological activity of the heatshock protein of 90 KDa (Hsp90) is dependent of its ATPase activity.Hsp90 is not only associated to the maintenance of cellular proteostasis,as the traditional chaperone role implies; it also plays a crucialrole in many cellular process and mechanisms. Therefore, it isnot surprising to find it associated to cell proliferation, migration, invasionand almost all the named ?hallmarks of cancer?. Cancer cellsare thought to be ?addicted? to this molecular chaperone showinghigh sensitivity to Hsp90 inhibitors compared to non-tumoral cells.Consequently, Hsp90 inhibitors are interesting for the developmentof new antitumoral therapies. Geldanamycin (GA) is a known Hsp90inhibitor, however it is not used in clinical treatments for its harmfulside effects. Nonetheless, GA was taken as base structure forthe development of potential non-toxic therapeutic agents. In previousworks we tested synthetic drugs design in silico as potentialHsp90 ATPase inhibitors. In this study, we focused on a group ofcompounds (named as series 4), which had shown an interestinginhibition of the ATPase activity, to evaluate their capability to affecta prostatic cancer model. In particular, compounds 4C, 4D, 4Fshow a reduction of the viability and migration of prostatic tumoralcells, with comparable effects to GA. However, while cell treatmentwith GA prevented steroid receptor nuclear import, all the syntheticdrugs were not active in this regard. These properties could havepharmacological relevance since the lack of side effects such assteroid receptor inactivation could not be desirable. Interestingly, ourresults contradicts the current dogma, i.e. drugs that affect the ATPaseactivity of Hsp90 show no effect in all the chaperone biologicalactivities. Consequently, these compounds could be used as basefor the development of potential new oncological therapies.