Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a
number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately,
results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance
resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns.
Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for
the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described,
which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel
approach to characterize Hsp90 inhibition in cancer cells.
Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays
(DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity
and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo
efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.
Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and
disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding
to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies
KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.
Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for
the treatment of prostate cancer.
Eskew, Jeffery D, Takrima Sadikot, Pedro Morales, Alicia Duren, Irene Dunwiddie, Megan Swink, Xiaoying Zhang, et al. 2011. “Development and Characterization of a Novel C-Terminal Inhibitor of Hsp90 in Androgen Dependent and Independent Prostate Cancer Cells.” BMC Cancer 11 (1) : 468. http://dx.doi.org/10.1186/1471-2407-11-468.