Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

Jeffery D Eskew, Takrima Sadikot, Pedro Morales, Alicia Duren, Irene Dunwiddie, Megan Swink, Xiaoying Zhang, Stacey Hembruff, Alison Donnelly, Roger A Rajewski, Brian SJ Blagg, Jacob R Manjarrez, Robert L Matts, Jeffrey M Holzbeierlein, George A Vielhauer

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.