title: Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
abstract: 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.
authors.affiliation: Chemistry and Earth & Ocean Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Simon
authors.initials: S
authors.lastname: Haile
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Myung
authors.forename: Kate
authors.initials: K
authors.lastname: Watt
authors.forename: Teresa
authors.initials: T
authors.lastname: Tam
authors.forename: Yu Chi
authors.initials: YC
authors.lastname: Yang
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Bañuelos
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Iain J
authors.initials: IJ
authors.lastname: McEwan
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Wang
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
mesh_terms: D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D050882:CREB-Binding Protein / Q000378:metabolism; D002369:Castration; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002728:Chlorohydrins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015394:Molecular Structure; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011487:Protein Conformation / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D001559:Benzhydryl Compounds; D002728:Chlorohydrins; C551471:EPI 001; D008024:Ligands; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D004247:DNA; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen