title: Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.
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.
authors: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors: Julie A
authors: JA
authors: Pollock
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Suzanne E
authors: SE
authors: Wardell
authors: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors: Alexander A
authors: AA
authors: Parent
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: David B
authors: DB
authors: Stagg
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Stephanie J
authors: SJ
authors: Ellison
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Holly M
authors: HM
authors: Alley
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Christina A
authors: CA
authors: Chao
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Scott A
authors: SA
authors: Lawrence
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: James P
authors: JP
authors: Stice
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.|Duke Cancer Institute, Pharmaceutical Research-PK/PD Core Laboratory, Durham, North Carolina, USA.
authors: Ivan
authors: I
authors: Spasojevic
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Jennifer G
authors: JG
authors: Baker
authors: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors: Sung Hoon
authors: SH
authors: Kim
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Donald P
authors: DP
authors: McDonnell
authors: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors: John A
authors: JA
authors: Katzenellenbogen
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: John D
authors: JD
authors: Norris
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D011944:Receptors, Androgen