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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 2016

Published In

Volume / Issue

  • 12 / 10

Start / End Page

  • 795 - 801

PubMed ID

  • 27501397

Pubmed Central ID

  • PMC5030124

Electronic International Standard Serial Number (EISSN)

  • 1552-4469

Digital Object Identifier (DOI)

  • 10.1038/nchembio.2131


  • eng

Conference Location

  • United States