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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.

Author information

1
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
3
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
4
Duke Cancer Institute, Pharmaceutical Research-PK/PD Core Laboratory, Durham, North Carolina, USA.

Abstract

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.

PMID:
27501397
PMCID:
PMC5030124
DOI:
10.1038/nchembio.2131
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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

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