Development of the C-Terminal Inhibitors of Heat Shock Protein 90 in the Treatment of Prostate Cancer

摘要

To develop and evaluate novel compounds which inhibit the C-terminal portion of Hsp90 in prostate cancer models. To develop a library of novobiocin analogues to be tested in vitro initially and then in a mouse model. Major findings: we have tested over 220 analogues of the original parent compound (A- 1) all of which have been tested in at least two commonly used prostate cancer cell lines LNCaP and PC3. Screening has been evaluated by both Western Blot of client proteins which include the androgen receptor, Akt, Hsp90, and HER2, and MTT assay. Furthermore, with our most effective compounds we have examined the mechanism of action and have examined cell cycle data. We have evaluated one compound in vivo and are currently evaluating our newest most promising compound in vivo in an orthotopic mouse model.