Effect of new HSP90 Inhibitors in two cancer models: prostate and breast cancer

SANTA CRUZ, I.; ARAMBURU, A.; ERLEJMAN, A.G.; CIUCCI, S. M.; GALIGNIANA, M.D.; MAZAIRA, G.I.

Mar del Plata

Congreso; LXVII Reunión anual de la Sociedad Argentina de Investigación Clínica(SAIC); 2022

Sociedad Argentina de Investigación Clínica

Hsp90 stabilizes the active conformation of cognate client proteins already exhibiting a stable tertiary structure, among them, steroid receptors and several oncoproteins. Cancer cells are dependent on chaperones given their elevated proteotoxic stress. Hsp90 inhibitors are to date the only known chemotherapeutic agent that shows strong effects in all hallmarks of cancer. Therefore, it is considered a promising molecular target for cancer treatment. Various Hsp90 inhibitors are being tested in clinical and preclinical studies with different results, but proven nephro- and hepatotoxic effects. The aim of this work was to analyze the biological actions of synthetic compounds predesigned by computational modeling according to the potential inhibitory effect on the intrinsic ATPase activity, which is regarded as essential for Hsp90 biological function. We assessed the effects of the drugs on the Hsp90 ATPase activity in vitro, cell viability and migration in two cancer cell models (prostate and breast), as well as their putative inhibitory action on the glucocorticoid receptor (GR) nuclear translocation. Geldanamycin (GA), a known Hsp90 inhibitor, was used as a positive control in all experiments. Pyrazoline-derivative compounds (C3 and C6) confirmed in silico predictions regarding their ability to inhibit Hsp90 ATPase activity. As expected, cell treatment with GA prevented nuclear import of the steroid receptor and decreased cell viability and cell migration capacity in both cell lines, PC3 (prostate cancer) and MDA-MB-231 (breast cancer). Both synthetic drugs also showed equivalent inhibitory action on cell viability and migration. Interestingly, none of the novel drugs showed any effect on the GR nuclear import. 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.