Abstract
Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.
Publication types
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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 Receptor Antagonists / chemistry
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Androgen Receptor Antagonists / pharmacology*
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Animals
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Antineoplastic Agents, Hormonal / chemistry
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Antineoplastic Agents, Hormonal / pharmacology*
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Benzhydryl Compounds / chemistry
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Benzhydryl Compounds / pharmacology*
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COS Cells
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Cell Proliferation / drug effects
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Chlorocebus aethiops
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Chlorohydrins / chemistry
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Chlorohydrins / pharmacology*
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Click Chemistry
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Gene Expression
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, Reporter
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Humans
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Luciferases / biosynthesis
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Luciferases / genetics
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Orchiectomy
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Binding
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Protein Structure, Tertiary
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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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Stereoisomerism
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Transcriptional Activation / drug effects
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Androgen Receptor Antagonists
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Antineoplastic Agents, Hormonal
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Benzhydryl Compounds
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Chlorohydrins
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EPI 001
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Receptors, Androgen
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Luciferases