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Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.

ABSTRACT: 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.

SUBMITTER: De Leon JT 

PROVIDER: S-EPMC3141981 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.

De Leon Johanny Tonos JT   Iwai Aki A   Feau Clementine C   Garcia Yenni Y   Balsiger Heather A HA   Storer Cheryl L CL   Suro Raquel M RM   Garza Kristine M KM   Lee Sunmin S   Kim Yeong Sang YS   Chen Yu Y   Ning Yang-Min YM   Riggs Daniel L DL   Fletterick Robert J RJ   Guy R Kiplin RK   Trepel Jane B JB   Neckers Leonard M LM   Cox Marc B MB  

Proceedings of the National Academy of Sciences of the United States of America 20110705 29

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 inhibito  ...[more]

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