Abstract
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.
Publication types
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Clinical Trial, Phase I
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Clinical Trial, Phase II
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Androgen Antagonists / metabolism
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Androgen Antagonists / pharmacokinetics
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Androgen Antagonists / pharmacology
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Androgen Antagonists / therapeutic use*
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Anilides / metabolism
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Anilides / pharmacology
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Benzamides
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Biological Availability
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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DNA / metabolism
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Male
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Mice
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Nitriles / metabolism
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Nitriles / pharmacology
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Phenylthiohydantoin / analogs & derivatives*
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Phenylthiohydantoin / metabolism
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Phenylthiohydantoin / pharmacokinetics
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Phenylthiohydantoin / pharmacology
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Phenylthiohydantoin / therapeutic use
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Receptors, Androgen / chemistry
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Tosyl Compounds / metabolism
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Tosyl Compounds / pharmacology
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Transcription, Genetic / drug effects
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Xenograft Model Antitumor Assays
Substances
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Androgen Antagonists
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Anilides
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Antineoplastic Agents
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Benzamides
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Nitriles
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RD162 compound
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Receptors, Androgen
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Tosyl Compounds
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Phenylthiohydantoin
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DNA
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enzalutamide
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bicalutamide