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

Autor: Pollock JA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Wardell SE; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Parent AA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Stagg DB; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Ellison SJ; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Alley HM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Chao CA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Lawrence SA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Stice JP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Spasojevic I; Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.; Duke Cancer Institute, Pharmaceutical Research-PK/PD Core Laboratory, Durham, North Carolina, USA., Baker JG; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Kim SH; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., McDonnell DP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Katzenellenbogen JA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Norris JD; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2016 Oct; Vol. 12 (10), pp. 795-801. Date of Electronic Publication: 2016 Aug 08.
DOI: 10.1038/nchembio.2131
Abstrakt: 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.
Competing Interests: Statement. A patent covering this work has been published (Publication No. WO 2015/048246).
Databáze: MEDLINE
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