title: Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.
abstract: Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling.
authors.affiliation: Department of Molecular Pharmacology, ‡Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center , Duarte, California 91010, United States of America.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lim
authors.forename: Maya
authors.initials: M
authors.lastname: Otto-Duessel
authors.forename: Miaoling
authors.initials: M
authors.lastname: He
authors.forename: Leila
authors.initials: L
authors.lastname: Su
authors.forename: Dan
authors.initials: D
authors.lastname: Nguyen
authors.forename: Emily
authors.initials: E
authors.lastname: Chin
authors.forename: Tamara
authors.initials: T
authors.lastname: Alliston
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
mesh_terms: D015502:Absorptiometry, Photon; D059002:Androgen Receptor Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D045744:Cell Line, Tumor; D019295:Computational Biology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008954:Models, Biological; D062105:Molecular Docking Simulation; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011774:Pyrvinium Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D008024:Ligands; D011774:Pyrvinium Compounds; D011944:Receptors, Androgen; C024631:pyrvinium