Non-competitive androgen receptor inhibition in vitro and in vivo
- Jeremy O. Jonesa,b,
- Eric C. Boltonb,
- Yong Huangc,
- Clementine Feaue,
- R. Kiplin Guye,
- Keith R. Yamamotob,
- Byron Hannd and
- Marc I. Diamonda,b,d,1
- aDepartments of Neurology,
- bCellular and Molecular Pharmacology, and
- cBiopharmaceutical Sciences, and
- dComprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94115; and
- eDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105
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Edited by David J. Mangelsdorf, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 5, 2009 (received for review July 25, 2008)
Abstract
Androgen receptor (AR) inhibitors are used to treat multiple human diseases, including hirsutism, benign prostatic hypertrophy, and prostate cancer, but all available anti-androgens target only ligand binding, either by reduction of available hormone or by competitive antagonism. New strategies are needed, and could have an important impact on therapy. One approach could be to target other cellular mechanisms required for receptor activation. In prior work, we used a cell-based assay of AR conformation change to identify non-ligand inhibitors of AR activity. Here, we characterize 2 compounds identified in this screen: pyrvinium pamoate, a Food and Drug Administration-approved drug, and harmol hydrochloride, a natural product. Each compound functions by a unique, non-competitive mechanism and synergizes with competitive antagonists to disrupt AR activity. Harmol blocks DNA occupancy by AR, whereas pyrvinium does not. Pyrvinium inhibits AR-dependent gene expression in the prostate gland in vivo, and induces prostate atrophy. These results highlight new therapeutic strategies to inhibit AR activity.
Footnotes
- 1To whom correspondence should be addressed. E-mail: marc.diamond{at}ucsf.edu
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Author contributions: J.O.J., B.H., and M.I.D. designed research; J.O.J., E.C.B., and B.H. performed research; Y.H., C.F., and R.K.G. contributed new reagents/analytic tools; J.O.J., E.C.B., Y.H., C.F., R.K.G., K.R.Y., B.H., and M.I.D. analyzed data; and J.O.J. and M.I.D. wrote the paper.
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Conflict of interest statement: Given the potential utility of pyrvinium and harmol as therapeutic agents, the University of California, San Francisco, has filed a novel use patent that claims these compounds. J.O.J. and M.I.D. are co-inventors on this patent, and will stand to profit if it is issued. To the extent that publication of this manuscript will increase the value of this patent, or the likelihood that it will be out-licensed, J.O.J. and M.I.D. have a potential conflict of interest.
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This article is a PNAS Direct Submission.
