To date, there are very limited therapies for patients with metastatic castrate resistant prostate cancer. Due to the heterogeneity of prostate cancer no one specific oncogene, mutation, signaling pathways, or risk factor has been described in prostate cancer. Multiple pathways have been described to contribute to both the development as well as progression of prostate cancer. Hsp90 has been shown to be over-expressed in prostate cancer and serves as a hub for multiple signaling pathways that contribute to malignant growth and proliferation, making it an excellent target for the development of inhibitors. In contrast to N-terminal inhibitors that induce the pro-survival heat shock response, C-terminal inhibitors do not, and therefore provide a new paradigm in cancer research. Specifically, we aim to prepare conformationally biased analogues of new Hsp90 C-terminal inhibitors, evaluate them through a series of novel assays in vitro, and then administer select compounds to an orthotopic model of prostate cancer to determine their efficacy. Upon completion of this project, we aim to produce compounds amenable to further evaluation in clinical trials for prostate cancer.
The development of cancer chemotherapeutics that target multiple pathways simultaneously represent an emerging paradigm in medicinal chemistry/drug design. Utilizing the techniques described in this application, inhibitors of the Hsp90-mediated protein folding process will be rationally developed with the aim of producing compounds that effectively block prostate cancer progression and growth and may be suitable for subsequent clinical evaluation.
|Moroni, Elisabetta; Zhao, Huiping; Blagg, Brian S J et al. (2014) Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities. J Chem Inf Model 54:195-208|
|Zhao, Jinbo; Zhao, Huiping; Hall, Jessica A et al. (2014) Triazole Containing Novobiocin and Biphenyl Amides as Hsp90 C-Terminal Inhibitors. Medchemcomm 5:1317-1323|
|Kusuma, Bhaskar Reddy; Khandelwal, Anuj; Gu, Wen et al. (2014) Synthesis and biological evaluation of coumarin replacements of novobiocin as Hsp90 inhibitors. Bioorg Med Chem 22:1441-9|