The biological activity of androgens, like other steroids, is mediated through the formation of a noncovalent receptor-steroid complex. A number of steroidal and nonsteroidal antiandrogens, which inhibit formation of this complex, are available for prostate cancer therapy. However, all of these agents act via reversible, competitive inhibition of androgen binding to the androgen receptor (AR). We recently reported on irreversible nonsteroidal antiandrogens and reversible selective androgen receptor modulators (SARMs). These discoveries provide the foundation for our hypothesis that irreversible SARMs will prove to be potent and selective therapeutic agents for the treatment of prostate cancer. We propose to design, synthesize, and explore the actions of these agents with prostate cancer cell lines using in vitro experiments and tumor xenografts in mice. We recognize that a number of pharmaceutical firms have shied away from developing new irreversible inhibitors of the AR. However, we believe that it is important to explore extensively the biological effects of irreversible AR ligands to define the best manner to treat prostate cancer and to understand the complex interaction between ligand and receptor. Irreversible SARMs provide a unique pharmacologic tool to do so. We propose to develop new and novel nonsteroidal irreversible SARMs and study their biological activity using a combination of in vitro and in vivo models in the presence of endogenous androgens. We purposefully avoid the use of commonly employed in vitro cotransfection models due to evidence in our labs demonstrating that these models are poor predictors of in vivo pharmacologic activity. We will use a combination of molecular modeling, organic synthesis, pharmacokinetics metabolism, and in vitro and in vivo studies with prostate cancer cell lines to provide an integrated investigation to understand the myriad factors that govern AR action for inhibition of prostate cancer growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK065227-03S1
Application #
7176486
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Mullins, Christopher V
Project Start
2003-08-15
Project End
2007-06-30
Budget Start
2006-03-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$20,541
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Hwang, Dong Jin; Yang, Jun; Xu, Huiping et al. (2006) Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer. Bioorg Med Chem 14:6525-38
Bohl, Casey E; Gao, Wenqing; Miller, Duane D et al. (2005) Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci U S A 102:6201-6