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

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

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Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Duke Cancer Institute, Pharmaceutical Research-PK/PD Core Laboratory, Durham, North Carolina, USA.


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.

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Conflict of interest statement

Statement. A patent covering this work has been published (Publication No. WO 2015/048246).

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