title: An androgen receptor N-terminal domain antagonist for treating prostate cancer.
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.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Myung
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Banuelos
authors.forename: Javier Garcia
authors.initials: JG
authors.lastname: Fernandez
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tien
authors.forename: Yu Chi
authors.initials: YC
authors.lastname: Yang
authors.forename: Iran
authors.initials: I
authors.lastname: Tavakoli
authors.forename: Simon
authors.initials: S
authors.lastname: Haile
authors.forename: Kate
authors.initials: K
authors.lastname: Watt
authors.forename: Iain J
authors.initials: IJ
authors.lastname: McEwan
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D002728:Chlorohydrins / Q000737:chemistry / Q000494:pharmacology*; D057930:Click Chemistry; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D015533:Transcriptional Activation / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D001559:Benzhydryl Compounds; D002728:Chlorohydrins; C551471:EPI 001; D011944:Receptors, Androgen; D008156:Luciferases