Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 29, Pages 11878-11883Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105160108
Keywords
immunophilin; FKBP4; steroid hormone receptor
Categories
Funding
- Border Biomedical Research Center's [National Center for Research Resources/National Institutes of Health (NIH)] [5G12RR008124]
- National Institute of General Medical Sciences, NIH [SC1GM084863]
- Research Initiative for Scientific Enhancement [R25GM069621]
- National Science Foundation [HRD-0832951]
- American Lebanese Syrian Associated Charities
- St. Jude Children's Research Hospital
- NIH [DK58080]
- Department of Defense [PC060344-W81XWH-07-1-0073]
- National Cancer Institute
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Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.
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