Introduction

The clinical success of new androgen receptor (AR)-targeted therapies in patients with castration-resistant prostate cancer (CRPC) emphasizes the continued importance of the AR signaling axis in the disease. Despite the use of this new generation of therapies, some men with CRPC do not respond and resistance to these therapies typically develops for those that do. Mechanisms attributed to the emergence of this non-responsive CRPC include the expression of splice variants of the AR (AR-SV), mutant forms of the AR, hyperactive AR, and others. The objective of this work is to develop selective androgen receptor degraders (SARDs) that degrade all forms of the AR and provide advanced treatment options to men with CRPC.

Methods

AR ligand binding, transactivation, fluorescence polarization, nuclear magnetic resonance (NMR), and Western blot assays were performed to screen novel SARDs. Prostate cancer cell line gene expression, proliferation, cell line and patient-derived xenografts (PDX) were performed to evaluate the efficacy of the SARDs. Molecular mechanistic studies were performed to understand the mechanism of action.

Results

This report details a novel series of highly potent SARDs that bind to the AR-LBD and inhibit transactivation at nM concentrations. One of the lead SARDs, UT-155 antagonizes AR with an IC₅₀ of 78nM in comparison to enzalutamide with an IC₅₀ of 465nM. In addition to their antagonistic activity, the SARDs degrade full-length, mutant and variant AR in the low μM range and inhibit the proliferation of AR-FL and AR-SV- dependent PCa cells with potencies better than that of the comparators. The SARDs robustly inhibit the growth of the LNCaP androgen-dependent prostate cancer (PCa) xenograft, the 22RV1 CRPC xenograft, and AR- and AR-SV- positive CRPC patient-derived xenografts (PDX). No significant toxicities have been observed in the animal studies that have been performed. NMR analysis as well fluorescence quenching support an interaction between the SARDs and the AR activation function domain (AF-1), making these molecules first-in-class dual-interacting AR antagonists and degraders.

Conclusions

Novel highly potent SARDs that interact with both AF-1 and LBD of the AR were discovered and characterized as a potential next-generation treatment option for advanced prostate cancer that is resistant to enzalutamide treatment. Clinical development of these compounds is ongoing.

Funding

GTx Inc.