title: Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells.
abstract: Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure-activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator-peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124-32. ©2016 AACR.
authors.affiliation: Department of Urology, New York University School of Medicine, New York, New York.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, New York University, New York, New York.
authors.forename: Dilani C
authors.initials: DC
authors.lastname: Dehigaspitiya
authors.affiliation: Department of Chemistry, New York University, New York, New York.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Levine
authors.affiliation: York College, Institute for Macromolecular Assemblies and the Graduate Center of the City University of New York, Jamaica, New York.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Profit
authors.affiliation: Department of Chemistry, New York University, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Haugbro
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York.
authors.forename: Keren
authors.initials: K
authors.lastname: Imberg-Kazdan
authors.affiliation: Department of Urology, New York University School of Medicine, New York, New York. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Logan
authors.affiliation: Department of Chemistry, New York University, New York, New York.
authors.forename: Kent
authors.initials: K
authors.lastname: Kirshenbaum
authors.affiliation: Department of Urology, New York University School of Medicine, New York, New York. Department of Microbiology, New York University School of Medicine, New York, New York. garabm01@med.nyu.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005003:Ethisterone / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009570:Nitriles; D034444:Peptoids / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D008024:Ligands; D009570:Nitriles; D034444:Peptoids; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; D005003:Ethisterone