Buenos Aires
Breast Cancer
Symposium

BA-BCS 2024

September 3 – 6, 2024

IFIBYNE Auditorium, FCEN-UBA

Poster No. 54

IN VITRO EFFECT OF NEW HSP90 INHIBITORS ON BREAST CANCER CELLS

Iara Sofía Santa Cruz1, Sol Ciucci2, Alejandra Erlejman2,3, Mario Galigniana1,2, Gisela Mazaira2,3

1.IByME-CONICET, Buenos Aires, Argenitna 2.epartamento de Química Biológica, FCEN, UBA. Buenos Aires, Argentina 3.IQUIBICEN/CONICET. Buenos Aires, Argentina .

Presenting Autor:
Santa Cruz, Iara Sofía

Lab. Receptores Nucelares, IByME - CONICET

Hsp90 maintains the active form of specific client proteins that already have a stable tertiary structure, including steroid receptors and various oncoproteins. Due to their high proteotoxic stress, cancer cells rely heavily on chaperones. Hsp90 inhibitors are the only chemotherapeutic agents known to strongly impact all hallmarks of cancer, making Hsp90 a promising target for cancer therapy. Numerous Hsp90 inhibitors are currently undergoing clinical and preclinical trials with varying results but have shown nephro- and hepatotoxicity. This study aimed to examine the biological actions of synthetic compounds designed via computational modelling for their potential inhibitory effect on Hsp90’s intrinsic ATPase activity, which is crucial for its function. We evaluated these compounds on Hsp90 ATPase activity in vitro, as well as on cell viability and migration in breast cancer models. Additionally, their potential to inhibit glucocorticoid receptor (GR) nuclear translocation was tested. Geldanamycin (GA), a known Hsp90 inhibitor, served as a positive control. Pyrazoline-derivative compounds (C3, C6, and 4F) confirmed in silico predictions by effectively inhibiting Hsp90 ATPase activity. As anticipated, GA treatment inhibited nuclear import of the steroid receptor in normal cells and reduced cell viability and migration in both MDA-MB-231 and MCF7 cell lines. The synthetic drugs similarly inhibited cell viability and migration but did not affect GR nuclear import in normal cells. Interestingly, the compounds were observed to affect cytoskeletal stability, resulting in a more adherent cell phenotype. This lack of effect on steroid receptor inhibition suggests these drugs could have significant pharmacological benefits, avoiding certain side effects. The study provides new insights that could aid in the development of more effective and less toxic drugs.