Abstract 4852: Multivalent peptoid conjugates suppress enzalutamide-resistant prostate cancer cellular proliferation

Abstract

Abstract Development of resistance to latest anti-androgens treatment for advanced prostate cancer is a growing concern. New strategies to block androgen receptor (AR) function in castration resistant prostate cancer are therefore required. Here we report the characterization of a multivalent conjugate presenting two spatially defined bioactive ethisterone ligands as spatially defined pendant groups on a peptoid oligomer. The conjugate, termed 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. Mechanistically, MPC6 blocked AR coactivator-peptide interaction, and decreased AR protein half-life. Pharmacological studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Importantly, 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. Citation Format: Yu Wang, Paul Levine, Dilani Dehigaspitiya, Adam Profit, Susan Logan, Keren Imberg-Kazdan, Kent Kirshenbaum, Michael Garabedian. Multivalent peptoid conjugates suppress enzalutamide-resistant prostate cancer cellular proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4852.