Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.

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.
Mesh Terms:
Androgen Receptor Antagonists, Androgens, Animals, Antineoplastic Agents, Hormonal, Apoptosis, Benzhydryl Compounds, CREB-Binding Protein, Castration, Cell Line, Tumor, Cell Proliferation, Chlorohydrins, DNA, Gene Expression, Humans, Ligands, Male, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Structure, Neoplasm Recurrence, Local, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Receptors, Androgen, Receptors, Steroid, Response Elements, Serine Endopeptidases, Transcriptional Activation, Xenograft Model Antitumor Assays
Cancer Cell
Date: Jun. 15, 2010
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