Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
Open accessAbstract
Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.
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EPI-001 treatment in androgen-dependent models including LNCaP xenografts in noncastrated hosts and the LTL313 renal capsule xenograft model leads to effective and specific inhibition of androgen receptor activity.
“EPI-001 treatment in AD models including LNCaP xenografts in noncastrated hosts and the LTL313 renal capsule xenograft model leads to effective and specific inhibition of AR activity (80).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [80]
EPI-001 targets the N-terminal domain of the androgen receptor.
“EPI-001 targets the NTD of the AR (80), whereas MDV 3100 binds to the LBD (81), similarly to bicalutamide.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [80]
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- Authors
- Andersen, R. J., Mawji, N. R., Wang, J., Wang, G., Haile, S., Myung, J.-K., Watt, K., Tam, T., Yang, Y. C., Bañuelos, C. A., Williams, D. E., McEwan, I. J., Wang, Y., & Sadar, M. D.
- Affiliations
- University of British Columbia (CA)
- BC Cancer Agency (CA)
- University of Aberdeen (GB)
- Corresponding author
- Sadar, Marianne D.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 17
- Issue
- 6
- Pages
- 535-546
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2118238803
- Cited by
- 503
- References
- 56
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 23 · 2023: 23 · 2022: 32 · 2021: 27 · 2020: 21 · 2019: 25 · 2018: 23 · 2017: 35 · 2016: 39 · 2015: 41 · 2014: 45 · 2013: 48 · 2012: 41
- FWCI
- 36.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP79308, MOP89902, PPP90150)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- castration-resistant prostate cancer, androgen receptor, N-terminal domain, small molecule inhibitors, protein-protein interaction inhibition, androgen response element
- MeSH terms
- Androgens, Animals, Benzhydryl Compounds, Castration, Chlorohydrins, DNA, Humans, Ligands, Male, Neoplasm Recurrence, Local, Prostate, Prostatic Neoplasms, Protein Binding, Protein Conformation, Receptors, Androgen, Receptors, Steroid, Serine Endopeptidases, Molecular Structure, Transcriptional Activation, Gene Expression, Mice, SCID, Mice, Inbred NOD, Apoptosis, Prostate-Specific Antigen, Antineoplastic Agents, Hormonal, Response Elements, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, CREB-Binding Protein, Mice, Protein Interaction Domains and Motifs, Protein Multimerization, Androgen Receptor Antagonists
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