Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging

Abstract

Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.

Keywords: antiproliferation; cancer; drug design; hormones; protein degradation.

Figure 1

Figure 1. (A) Structures of Selective Androgen Receptor Degraders (SARDs) based on the androgen receptor agonist RU59063. (B) Immunoblot analyses of LNCaP human prostate tumor cells incubated with SARDS or parent ligand for 24 hours.

Figure 2

SARDs block human prostate cancer cells (LNCaP) as well as MDV3100. LNCaP cell proliferation assay in the presence of indicated compounds at 3 μM. The assay was performed in 10% FBS, and viable cells were counted at each indicated day.

Figure 3

SARD279 has more antiproliferative activity than MDV3100 in the presence of low androgen levels. LNCaP cells supplemented with 1 nM of the AR agonist R1881 were incubated for 7-days with MDV3100 or SARD279 after which cell proliferation was measured. The growth media contained 5% charcoal stripped FBS to eliminate exogenous androgens.

Figure 4

SARD-mediated antiproliferative activity in MDV3100-resistant cells. LNCaP/AR-F876L cells were incubated with indicated doses of MDV3100 or SARD279 for 7 days in the presence of 5% charcoal stripped FBS.