Pharmacological Inhibitors of the molecular chaperone HSP90

CIUCCI, SOL M.; ERLEJMAN A.G.; GALIGNIANA M.D.; MAZAIRA G.I.

Virtual

Congreso; LXV Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC) en el marco de la Reunión Conjunta de Sociedades de Biociencias; 2020

Sociedad Argenitna de Investigación Clínica

Hsp90 is a molecular chaperone that stabilizes in an ATP-dependentmanner the active conformation of many proteins with stable tertiarystructure. Several substrate proteins of this chaperone are relatedto tumor development and progression, hence making Hsp90 an attractivetarget for antitumor therapy. The inhibition of Hsp90 activityshows strong anticancer effects, and Hsp90 inhibitors seem to bethe 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 harmfulside-effects.In the present work we evaluated the capability of synthetized compoundsdesigned by molecular modelling to inhibit the ATPase activityof Hsp90, and their effects on the biological actions mediatedby this chaperone, such as PC3 cell viability and migration, aswell as GR transport to the nucleus after hormonal stimulation inHEK293T-transfected cells. In all the cases, GA was used as aninhibitory control. Nine compounds named S3, S8, S31, S42, A15,C3, C6, N15 and P1 were tested. All of them confirmed the in silicopredictions regarding their ability to inhibit the intrinsic ATPaseactivity of Hsp90. The S-series of dihydroxybenzaldheyde-derivedSchiff bases and C-series of pyrazoline-derived drugs (especiallyC3 and C6) showed a decreased action on cell viability comparableto that shown by GA, but only S3, S8, S31 and S42 decreased cellmigration comparable to the positive control. None of the syntheticsdrugs affected the GR nuclear import.In summary, in this study we described various synthetic candidateswith high pharmacological potential. Importantly, it is also shown thatHsp90 ATPase activity is not an essential requirement for cell viabilityand GR nuclear import, which opposites the prevailing dogma.