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Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.

Publication ,  Journal Article
Joseph, JD; Wittmann, BM; Dwyer, MA; Cui, H; Dye, DA; McDonnell, DP; Norris, JD
Published in: Proc Natl Acad Sci U S A
July 21, 2009

The impact of ligand binding on nuclear receptor (NR) structure and the ability of target cells to distinguish between different receptor-ligand complexes are key determinants of the pharmacological activity of NR ligands. However, until relatively recently, these mechanistic insights have not been used in a prospective manner to develop screens for NR modulators with specific therapeutic activities. Driven by the need for unique androgen receptor (AR) antagonists that retain activity in hormone-refractory prostate cancer, we developed and applied a conformation-based screen to identify AR antagonists that were mechanistically distinct from existing drugs of this class. Two molecules were identified by using this approach, D36 and D80, which interact with AR in a unique manner and allosterically inhibit AR agonist activity. Unlike the clinically important antiandrogens, casodex and hydroxyflutamide, both D36 and D80 block androgen action in cellular models of hormone-refractory prostate cancer. Mechanistically, these compounds further distinguish themselves from classical AR antagonists in that they do not promote AR nuclear translocation and quantitatively inhibit the association of AR with DNA even under conditions of overexpression. Although the therapeutic potential of these antiandrogens is apparent, it is the demonstration that it is possible, to modulate the interaction of cofactors with agonist-activated AR, using second-site modulators, that has the greatest potential with respect to the therapeutic exploitation of AR and other NRs.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 21, 2009

Volume

106

Issue

29

Start / End Page

12178 / 12183

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Molecular Conformation
  • Mice
  • Male
  • Ligands
  • Humans
  • Drug Screening Assays, Antitumor
  • Drug Resistance, Neoplasm
 

Citation

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Joseph, J. D., Wittmann, B. M., Dwyer, M. A., Cui, H., Dye, D. A., McDonnell, D. P., & Norris, J. D. (2009). Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists. Proc Natl Acad Sci U S A, 106(29), 12178–12183. https://doi.org/10.1073/pnas.0900185106
Joseph, James D., Bryan M. Wittmann, Mary A. Dwyer, Huaxia Cui, Delita A. Dye, Donald P. McDonnell, and John D. Norris. “Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.Proc Natl Acad Sci U S A 106, no. 29 (July 21, 2009): 12178–83. https://doi.org/10.1073/pnas.0900185106.
Joseph JD, Wittmann BM, Dwyer MA, Cui H, Dye DA, McDonnell DP, et al. Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12178–83.
Joseph, James D., et al. “Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.Proc Natl Acad Sci U S A, vol. 106, no. 29, July 2009, pp. 12178–83. Pubmed, doi:10.1073/pnas.0900185106.
Joseph JD, Wittmann BM, Dwyer MA, Cui H, Dye DA, McDonnell DP, Norris JD. Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12178–12183.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 21, 2009

Volume

106

Issue

29

Start / End Page

12178 / 12183

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Molecular Conformation
  • Mice
  • Male
  • Ligands
  • Humans
  • Drug Screening Assays, Antitumor
  • Drug Resistance, Neoplasm