title: Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.
abstract: Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gustafson
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Taavi K
authors.initials: TK
authors.lastname: Neklesa
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Carly S
authors.initials: CS
authors.lastname: Cox
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Anke G
authors.initials: AG
authors.lastname: Roth
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Hyun Seop
authors.initials: HS
authors.lastname: Tae
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA).
authors.forename: D Blake
authors.initials: DB
authors.lastname: Stagg
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA).
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA).
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA). craig.crews@yale.edu.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D017354:Point Mutation; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: antiproliferation; cancer; drug design; hormones; protein degradation