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Development of a second-generation antiandrogen for treatment of advanced prostate cancer.
Open accessAbstract
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
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“The ability of these molecules to inhibit AR transcriptional activity and demonstrate clinical efficacy in a phase I/II trial of patients with CR tumors, in the case of MDV 3100, suggests that ligand-directed therapeutics might still have a place in future treatment regimes.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [81]
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“The ability of these molecules to inhibit AR transcriptional activity and demonstrate clinical efficacy in a phase I/II trial of patients with CR tumors, in the case of MDV 3100, suggests that ligand-directed therapeutics might still have a place in future treatment regimes.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [81]
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“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 [81]
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“The ARE repeat reporter (4X-ARE, firefly luciferase) has been previously described (Tran et al., 2009).”
From Allosteric interactions prime androgen receptor dimerization and activation (2022) · cites this paper as Tran et al., 2009
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Metadata
- Authors
- Tran, C., Ouk, S., Clegg, N. J., Chen, Y., Watson, P. A., Arora, V., Wongvipat, J., Smith-Jones, P. M., Yoo, D., Kwon, A., Wasielewska, T., Welsbie, D., Chen, C. D., Higano, C. S., Beer, T. M., Hung, D. T., Scher, H. I., Jung, M. E., & Sawyers, C. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- University of Washington (US)
- Oregon Health & Science University (US)
- Medivation, Inc. (United States) (US)
- Corresponding author
- Tran, Chris
- Ouk, Samedy
- Chen, Charlie Degui
- Jung, Michael E.
- Sawyers, Charles L.
- ORCID
- Venue
- Science
- Published
- 2009-05-08
- Volume
- 324
- Issue
- 5928
- Pages
- 787-790
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2981508
- OpenAlex
- W2119504728
- Cited by
- 2,292
- References
- 21
- Citations by year
- 2026: 58 · 2025: 91 · 2024: 110 · 2023: 141 · 2022: 139 · 2021: 150 · 2020: 152 · 2019: 131 · 2018: 146 · 2017: 145 · 2016: 157 · 2015: 134 · 2014: 163 · 2013: 163 · 2012: 160
- FWCI
- 116.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA092629)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- castration-resistant prostate cancer, androgen receptor antagonists, enzalutamide, androgen receptor, bicalutamide, nonsteroidal antiandrogens, androgen receptor nuclear translocation, coactivator recruitment, prostate-specific antigen, oral anticancer drugs, drug development
- MeSH terms
- Androgen Antagonists, Anilides, Animals, Antineoplastic Agents, Benzamides, Biological Availability, Cell Nucleus, DNA, Drug Screening Assays, Antitumor, Humans, Male, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Receptors, Androgen, Tosyl Compounds, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice
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