Abstract
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abiraterone Acetate
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Androgen Receptor Antagonists / metabolism
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Androgen Receptor Antagonists / pharmacology*
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Androstadienes / pharmacology
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Benzamides
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Cell Line, Tumor
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Disease Models, Animal
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Down-Regulation
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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Humans
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Male
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Mice
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Mice, Nude
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Nitriles
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Phenylthiohydantoin / analogs & derivatives
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Phenylthiohydantoin / pharmacology
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / pathology*
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Pyridazines / chemical synthesis
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Pyridazines / metabolism
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Pyridazines / pharmacology*
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Rats
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Rats, Wistar
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Seminal Vesicles / drug effects*
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Seminal Vesicles / growth & development
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
Substances
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AZD3514
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Androgen Receptor Antagonists
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Androstadienes
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Antineoplastic Agents
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Benzamides
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Nitriles
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Pyridazines
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Receptors, Androgen
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Phenylthiohydantoin
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enzalutamide
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Abiraterone Acetate