title: Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells.
abstract: 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.
authors: The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Jeffery D
authors: JD
authors: Eskew
authors: Takrima
authors: T
authors: Sadikot
authors: Pedro
authors: P
authors: Morales
authors: Alicia
authors: A
authors: Duren
authors: Irene
authors: I
authors: Dunwiddie
authors: Megan
authors: M
authors: Swink
authors: Xiaoying
authors: X
authors: Zhang
authors: Stacey
authors: S
authors: Hembruff
authors: Alison
authors: A
authors: Donnelly
authors: Roger A
authors: RA
authors: Rajewski
authors: Brian S J
authors: BS
authors: Blagg
authors: Jacob R
authors: JR
authors: Manjarrez
authors: Robert L
authors: RL
authors: Matts
authors: Jeffrey M
authors: JM
authors: Holzbeierlein
authors: George A
authors: GA
authors: Vielhauer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009675:Novobiocin / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D009675:Novobiocin