Development of resistance to anti-androgens 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 anti-proliferative 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. Pharmacological 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.
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Cancer research. 2016 Aug 03 [Epub ahead of print]
Yu Wang, Dilani C Dehigaspitiya, Paul M Levine, Adam A Profit, Michael Haugbro, Keren Imberg-Kazdan, Susan K Logan, Kent Kirshenbaum, Michael J Garabedian
Urology, New York University School of Medicine., Chemistry, New York University., Chemistry, New York University., Chemistry, York College., Chemistry, New York University., Microbiology, New York University School of Medicine., Urology and Pharmacology, New York University School of Medicine., Chemistry, New York University., Microbiology, New York University School of Medicine .