This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kazmin, D. Articles by McDonnell, D. P. Search for Related Content PubMed PubMed Citation Articles by Kazmin, D. Articles by McDonnell, D. P.

Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor Modulators

Department of Pharmacology and Cancer Biology (D.K., J.D.N., C.-y.C., D.P.M.), Duke University Medical Center, and Department of Chemistry (T.P., D.B.), Duke University, Durham, North Carolina 27710; Science and Engineering Group (C.E.C.), Research Triangle Institute, Research Triangle Park, North Carolina 27709; and SAS Institute (R.W., T.-M.C.), Cary, North Carolina 27513

Address all correspondence and requests for reprints to: Donald P. McDonnell, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710. E-mail: donald.mcdonnell{at}duke.edu.

We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   ARA54  |  NCOR

Ligands:   Dihydrotestosterone  |  R1881

This article has been cited by other articles:

				D. E. Frigo, A. B. Sherk, B. M. Wittmann, J. D. Norris, Q. Wang, J. D. Joseph, A. P. Toner, M. Brown, and D. P. McDonnell Induction of Kruppel-Like Factor 5 Expression by Androgens Results in Increased CXCR4-Dependent Migration of Prostate Cancer Cells in Vitro Mol. Endocrinol., September 1, 2009; 23(9): 1385 - 1396. [Abstract] [Full Text] [PDF]

				R. Jasuja, J. Ulloor, C. M. Yengo, K. Choong, A. Y. Istomin, D. R. Livesay, D. J. Jacobs, R. S. Swerdloff, J. Miksovska, R. W. Larsen, et al. Kinetic and Thermodynamic Characterization of Dihydrotestosterone-Induced Conformational Perturbations in Androgen Receptor Ligand-Binding Domain Mol. Endocrinol., August 1, 2009; 23(8): 1231 - 1241. [Abstract] [Full Text] [PDF]

				J. O. Jones, E. C. Bolton, Y. Huang, C. Feau, R. K. Guy, K. R. Yamamoto, B. Hann, and M. I. Diamond Non-competitive androgen receptor inhibition in vitro and in vivo PNAS, April 28, 2009; 106(17): 7233 - 7238. [Abstract] [Full Text] [PDF]

				P. Mendiratta, E. Mostaghel, J. Guinney, A. K. Tewari, A. Porrello, W. T. Barry, P. S. Nelson, and P. G. Febbo Genomic Strategy for Targeting Therapy in Castration-Resistant Prostate Cancer J. Clin. Oncol., April 20, 2009; 27(12): 2022 - 2029. [Abstract] [Full Text] [PDF]

				V. C. Jordan A Century of Deciphering the Control Mechanisms of Sex Steroid Action in Breast and Prostate Cancer: The Origins of Targeted Therapy and Chemoprevention Cancer Res., February 15, 2009; 69(4): 1243 - 1254. [Abstract] [Full Text] [PDF]

				A. B. Sherk, D. E. Frigo, C. G. Schnackenberg, J. D. Bray, N. J. Laping, W. Trizna, M. Hammond, J. R. Patterson, S. K. Thompson, D. Kazmin, et al. Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic Cancer Res., September 15, 2008; 68(18): 7475 - 7483. [Abstract] [Full Text] [PDF]

				D. E. Frigo and D. P. McDonnell Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation Mol. Cancer Ther., March 1, 2008; 7(3): 659 - 669. [Abstract] [Full Text] [PDF]

				S. Chouinard, O. Barbier, and A. Belanger UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells J. Biol. Chem., November 16, 2007; 282(46): 33466 - 33474. [Abstract] [Full Text] [PDF]

				W. Gao and J. T. Dalton Ockham's Razor and Selective Androgen Receptor Modulators (SARMs): Are We Overlooking the Role of 5{alpha}-Reductase? Mol. Interv., February 1, 2007; 7(1): 10 - 13. [Abstract] [Full Text] [PDF]

				J. Ostrowski, J. E. Kuhns, J. A. Lupisella, M. C. Manfredi, B. C. Beehler, S. R. Krystek Jr., Y. Bi, C. Sun, R. Seethala, R. Golla, et al. Pharmacological and X-Ray Structural Characterization of a Novel Selective Androgen Receptor Modulator: Potent Hyperanabolic Stimulation of Skeletal Muscle with Hypostimulation of Prostate in Rats Endocrinology, January 1, 2007; 148(1): 4 - 12. [Abstract] [Full Text] [PDF]