title: Multivalent peptidomimetic conjugates: a versatile platform for modulating androgen receptor activity.
abstract: We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.
authors.affiliation: Department of Chemistry, New York University, New York, New York 10003, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Levine
authors.forename: Keren
authors.initials: K
authors.lastname: Imberg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.forename: Kent
authors.initials: K
authors.lastname: Kirshenbaum
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010455:Peptides; D011944:Receptors, Androgen