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. Ó2016 AACR.

Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

“…Peptidomimetic conjugates (MCPs) are peptoids that display bioactive ligands and are resistant to proteases (63, 64). Such conjugates have been used to antagonize AR.…”

“…Such conjugates have been used to antagonize AR. MCPs, such as MCP6, prevent intermolecular interactions between AR and its coactivators by changing the AR conformation (64). However, MCP6 shows no effect in the human CRPC cell line 22Rv1.…”

“…However, MCP6 shows no effect in the human CRPC cell line 22Rv1. The reason MCP6 fails to inhibit AR-V-containing 22Rv1 may be that MCP6 competes for androgen binding to the AR LBD (64), and may not interfere with binding of coactivators to the NTD. Similarly, the peptidomimetics used by Ravindranathan et al ., 2013 (65) disrupt the interaction between FL-AR LBD and its coactivators.…”

Rationale for the development of alternative forms of androgen deprivation therapy

“…Along the same lines, peptidomimetics have been developed that are able to disrupt interaction between AR and its coregulator PELP1 in several preclinical CaP models and ex vivo CaP explants (Ravindranathan, et al 2013). Similarly, multivalent peptoid conjugates that block AR coactivator-peptide interactions and prevent AR intermolecular interactions reduced proliferation of CR-CaP cell lines and reduced tumor growth, and AR and Ki67 expression in CR-CaP xenografts (Levine, et al 2012; Wang, et al 2016). While the above mentioned tactics strive to disrupt specific AR-protein interactions, successful attempts have been made also at disruption the interaction between AR and AREs and between AR-associated transcription factors and their consensus binding motifs.…”

Nanoparticle delivery of RNA‐based therapeutics to alter the vocal fold tissue response to injury

“…6,23 Peptoids are a class of peptidomimetic, Nsubstituted glycine oligomers with a range of biomedical applications. [24][25][26][27] A family of sequence-specific peptoids bearing cationic side-chains and conjugated to phospholipid tails have been investigated as transfection agents and are referred to as lipitoids. 28 The structure of a representative lipitoid is shown in Figure 1.…”