Scholars@Duke

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.

Publication ,  Journal Article
Pollock, JA; Wardell, SE; Parent, AA; Stagg, DB; Ellison, SJ; Alley, HM; Chao, CA; Lawrence, SA; Stice, JP; Spasojevic, I; Baker, JG; Kim, SH ...
Published in: Nat Chem Biol
October 2016
Published version (DOI) Link to item

Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR-CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.

Duke Scholars

Suzanne E Wardell
Author Suzanne E Wardell Pharmacology & Cancer Biology
Ivan Spasojevic
Author Ivan Spasojevic Medicine, Medical Oncology
Donald Patrick McDonnell
Author Donald Patrick McDonnell Pharmacology & Cancer Biology
John David Norris
Author John David Norris Pharmacology & Cancer Biology

Published In

Nat Chem Biol

DOI

10.1038/nchembio.2131

EISSN

1552-4469

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

795 / 801

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Male
  • Humans
  • Drug Screening Assays, Antitumor
  • Dose-Response Relationship, Drug
  • Cell Proliferation
  • Cell Nucleus
  • Biochemistry & Molecular Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Pollock, J. A., Wardell, S. E., Parent, A. A., Stagg, D. B., Ellison, S. J., Alley, H. M., … Norris, J. D. (2016). Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. Nat Chem Biol, 12(10), 795–801. https://doi.org/10.1038/nchembio.2131
Pollock, Julie A., Suzanne E. Wardell, Alexander A. Parent, David B. Stagg, Stephanie J. Ellison, Holly M. Alley, Christina A. Chao, et al. “Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.” Nat Chem Biol 12, no. 10 (October 2016): 795–801. https://doi.org/10.1038/nchembio.2131.
Pollock JA, Wardell SE, Parent AA, Stagg DB, Ellison SJ, Alley HM, et al. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. Nat Chem Biol. 2016 Oct;12(10):795–801.
Pollock, Julie A., et al. “Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.” Nat Chem Biol, vol. 12, no. 10, Oct. 2016, pp. 795–801. Pubmed, doi:10.1038/nchembio.2131.
Pollock JA, Wardell SE, Parent AA, Stagg DB, Ellison SJ, Alley HM, Chao CA, Lawrence SA, Stice JP, Spasojevic I, Baker JG, Kim SH, McDonnell DP, Katzenellenbogen JA, Norris JD. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. Nat Chem Biol. 2016 Oct;12(10):795–801.

Published In

Nat Chem Biol

DOI

10.1038/nchembio.2131

EISSN

1552-4469

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

795 / 801

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Male
  • Humans
  • Drug Screening Assays, Antitumor
  • Dose-Response Relationship, Drug
  • Cell Proliferation
  • Cell Nucleus
  • Biochemistry & Molecular Biology