Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

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

doi:10.1038/nchembio.2131

Cited by 16 publications

(16 citation statements)

References 45 publications

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“…Cells were stained for the AR and analyzed by high-content imaging as described previously (42). Briefly, HEK293 or VCAP cells were fixed with 4% paraformaldehyde, permeabilized with Triton X-100 (0.1%), stained for AR expression (1:400, N-20; Santa Cruz Biotechnology Inc.), and counterstained for DNA (DAPI; Sigma-Aldrich) and F-actin (rhodamine phalloidin; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…HepG2 cells were maintained in Basal Medium Eagle (Sigma Aldrich) containing 8% FBS. For mammalian 2-hybrid-based AR cofactor assays (41,42), cells were seeded in 96-well plates and transfected with VP16-AR (900 ng), 5XGalLuc3 (900 ng), Gal4-interactor (900 ng), and Renilla-Luc (300 ng) using Lipofectin (Thermo Fisher Scientific). Cells were then treated with the ligands as indicated in Figure legend 3 for 48 hours, at which point, dual-luciferase assays were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we reported on the development and validation of a cell-based AR conformationprofiling tool that utilizes peptide probes derived from nuclear receptor coregulators to survey ligand-induced alterations on the surface of the receptor (41,42). This tool leverages the observation that receptor conformation, a primary determinant of coregulator recruitment, is predictive of the pharmacological activity of AR ligands.…”

Section: Cyp17 Inhibitors Directly Bind and Antagonize Ar Activitymentioning

confidence: 99%

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Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Norris

Ellison

Baker

et al. 2017

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cyp17 Inhibitors Directly Bind and Antagonize Ar Activitymentioning

confidence: 99%

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Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Norris

Ellison

Baker

et al. 2017

Journal of Clinical Investigation

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“…The reason why the AR-LBD crystal structure could not be resolved and what is unique about the AR-LBD that prevents its structural elucidation, remains important unanswered questions. The only information that is currently available comes from limited trypsinization studies and cofactor-interaction profiling that indicate that the AR conformation in the presence of agonists and antagonists is distinct [ 79 , 80 ].…”

Section: Armentioning

confidence: 99%

Therapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer

Narayanan

2020

Asian Journal of Urology

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Prostate cancer (PCa) accounted for over 300 000 deaths world-wide in 2018. Most of the PCa deaths occurred due to the aggressive castration-resistant PCa (CRPC). Since the androgen receptor (AR) and its ligands contribute to the continued growth of androgen-dependent PCa (ADPCa) and CRPC, AR has become a well-characterized and pivotal therapeutic-target. Although AR signaling was identified as therapeutic-target in PCa over five-decades ago, there remains several practical issues such as lack of antagonist-bound AR crystal structure, stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction, unfavorable large-molecule accommodation of the ligand-binding domain (LBD), and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs. This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future AR-targeted drug development of potent next-generation molecules. The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.

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“…The core ligand of cyclobutane, which was used as the fourth-generation antiandrogen drug, might be of great importance in CRPC therapy through inhibition of nuclear translocation of AR. 86 …”

Section: The New Advancement Of Crpc Therapymentioning

confidence: 99%

Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer

Wang

Ruan

et al. 2018

OTT

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BackgroundAlthough there have been great advances in mechanisms and therapeutic methods of prostate cancer, the mortality rate of prostate cancer remains high. The castration-resistant prostate cancer (CRPC), which develops from hormone-sensitive prostate cancer, foreshadows a more dismal outcome. Concomitant with the researches in the mechanism of CRPC and therapy for CRPC, more and more landmark progress has been made in recent years.MethodsA number of clinical and experimental studies were reviewed to indicate the novel advancement in the progressive mechanism and therapy of CRPC.ResultsThe androgen receptor (AR) is still a vital driver in the progression of CRPC, while other multiple mechanisms also contribute to this progression, such as tumor immunity, cancer stem cells, epithelial–mesenchymal transition and DNA repair disorder. In terms of the therapeutic methods of CRPC, chemotherapy with drugs, such as docetaxel, has been the first-line therapy for CRPC for many years. Besides, newer agents, which target some of the above mechanisms, show additional overall survival benefits for CRPC patients. These therapies include drugs targeting the androgen axis pathway (androgen synthesis, androgen receptor splice variants, coactivators of AR and so on), PI3K-AKT pathway, WNT pathway, DNA repair, rearrangement of ETS gene, novel chemotherapy and immunotherapy, bone metastasis therapy and so on. Understanding these novel findings on the mechanisms of CRPC and the latest potential CRPC therapies will direct us for further exploration of CRPC.ConclusionThrough comprehensive consideration, the predominant mechanism of CRPC might be the AR signal axis concomitant with tumor microenvironment, stress, immunity, tumor microenvironment and so on. For CRPC therapy, targeting the AR axis pathway and chemotherapy are the first-line treatments at present. However, with the advancements in CRPC therapy made by the researchers, other novel potential methods will occupy more and more important position in the treatment of CRPC, especially the therapies targeting the tumor microenviroment, tumor immunity and DNA repair and so on.

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Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Cited by 16 publications

References 45 publications

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Therapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer

Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer

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