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: Julie A Pollock, Suzanne E Wardell, Alexander A Parent, David B Stagg, Stephanie J Ellison, Holly M Alley, Christina A Chao, Scott A Lawrence, James P Stice, Ivan Spasojevic, Jennifer G Baker, Sung Hoon Kim, Donald P McDonnell, John A Katzenellenbogen, John D Norris
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 12 Issue 10 Pg. 795-801 (10 2016) ISSN: 1552-4469 [Electronic] United States
• PMID: 27501397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgen Receptor Antagonists
• Antineoplastic Agents
• Receptors, Androgen

Topics

• Androgen Receptor Antagonists (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Male
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Receptors, Androgen (metabolism)
• Structure-Activity Relationship