title: "True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer.
abstract: Prostate cancer (PCa) therapy typically involves administration of "classical" antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.
authors.affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Laura
authors.initials: L
authors.lastname: Caboni
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.forename: Fernando
authors.initials: F
authors.lastname: Blanco
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
authors.forename: William N
authors.initials: WN
authors.lastname: Jagoe
authors.forename: Miriam
authors.initials: M
authors.lastname: Carr
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005454:Fluorescence Polarization; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006834:Hydrazines; D056918:Nuclear Receptor Coactivators; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D017430:Prostate-Specific Antigen