Pharmacological inhibitors of the molecular chaperone Hsp90

ERLEJMAN A; GALIGNIANA MD; CIUCCI S; MAZAIRA G

Virtual

Congreso; LXV Reunión Anual de SAIC; 2020

SAIC

Hsp90 is a molecular chaperone that stabilizes in an ATP-dependent manner the active conformation of many proteins with stable tertiary structure. Several substrate proteins of this chaperone are related to tumor development and progression, hence making Hsp90 an attractive target for antitumor therapy. The inhibition of Hsp90 activity shows strong anticancer effects, and Hsp90 inhibitors seem to be the only chemotherapeutic agents capable to affect all cancer hallmarks. Unfortunately, one of the most efficient inhibitors, Geldanamycin (GA), cannot be used in clinical trials because of its harmful side-effects. In the present work we evaluated the capability of synthetized compounds designed by molecular modelling to inhibit the ATPase activity of Hsp90, and their effects on the biological actions mediated by this chaperone, such as PC3 cell viability and migration, as well as GR transport to the nucleus after hormonal stimulation in HEK293T-transfected cells. In all the cases, GA was used as an inhibitory control. Nine compounds named S3, S8, S31, S42, A15, C3, C6, N15 and P1 were tested. All of them confirmed the in silico predictions regarding their ability to inhibit the intrinsic ATPase activity of Hsp90. The S-series of dihydroxybenzaldheyde-derived Schiff bases and C-series of pyrazoline-derived drugs (especially C3 and C6) showed a decreased action on cell viability comparable to that shown by GA, but only S3, S8, S31 and S42 decreased cell migration comparable to the positive control. None of the synthetics drugs affected the GR nuclear import. In summary, in this study we described various synthetic candidates with high pharmacological potential. Importantly, it is also shown that Hsp90 ATPase activity is not an essential requirement for cell viability and GR nuclear import, which opposites the prevailing dogma.