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

Authors: Pollock, Julie A; Wardell, Suzanne E; Parent, Alexander A; Stagg, David B; Ellison, Stephanie J; Alley, Holly M; Chao, Christina A; Lawrence, Scott A; Stice, James P; Spasojevic, Ivan; Baker, Jennifer G; Kim, Sung Hoon; McDonnell, Donald P; Katzenellenbogen, John A; Norris, John D

Published In Nat Chem Biol, (2016 Oct)

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.

PubMed ID: 27501397

MeSH Terms: No MeSH terms associated with this publication