Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Nat Chem Biol. 2016 Oct;12(10):795-801. doi: 10.1038/nchembio.2131. Epub 2016 Aug 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptors, Androgen / metabolism*
  • Structure-Activity Relationship


  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Receptors, Androgen

Associated data

  • PubChem-Substance/315659261
  • PubChem-Substance/315659262
  • PubChem-Substance/315659263
  • PubChem-Substance/315659264
  • PubChem-Substance/315659265
  • PubChem-Substance/315659266
  • PubChem-Substance/315659267
  • PubChem-Substance/315659268
  • PubChem-Substance/315659269
  • PubChem-Substance/315659270
  • PubChem-Substance/315659271
  • PubChem-Substance/315659272
  • PubChem-Substance/315659273
  • PubChem-Substance/315659274
  • PubChem-Substance/315659275
  • PubChem-Substance/315659276
  • PubChem-Substance/315659277
  • PubChem-Substance/315659278
  • PubChem-Substance/315659279
  • PubChem-Substance/315659280
  • PubChem-Substance/315659281
  • PubChem-Substance/315659282
  • PubChem-Substance/315659283
  • PubChem-Substance/315659284
  • PubChem-Substance/315659285
  • PubChem-Substance/315659286
  • PubChem-Substance/315659287
  • PubChem-Substance/315659288
  • PubChem-Substance/315659289