Molecules targeting the androgen receptor (AR) signaling axis beyond the AR-Ligand binding domain

Abstract

Prostate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR-LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR-TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge-derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies.

Keywords: androgen receptor; androgen receptor DNA-binding domain; androgen receptor degradation; androgen receptor signaling axis; androgen receptor transactivation domain; castration-resistant prostate cancer; prostate cancer.

Figure 1.

A) Hormonal regulation of androgen production by the hypothalamus B) AR-dependent gene expression and effect of AR antagonists C) Full length androgen receptor (AR_FL) and the clinically relevant splice variants (AR_SVs) AR-V7 and AR-V12.^, Full length receptor has three distinct domains (C-terminal ligand binding – LBD, DNA binding – DBD, and N-terminal transactivation – TAD/NTD) while the splice variants lack a functional ligand binding domain. Most splice variants such as AR-V7 are constitutively active. (HR = hinge region, NLS = nuclear localization signal)

Figure 2.

Progression and the different stages of prostate cancer. While the currently available therapies (commonly used ones indicated in the figure) are quite responsive at the hormone-sensitive stages, metastatic castration-resistant disease has a poor prognosis. Figure updated and redrawn from reference. (P = prednisone, CBZ = cabazitaxel)

Figure 3.

Structures of hairpin polyamides PA1, PA2, and Ac-PA1. PA1 is designed to bind the ARE sequence 5′-AGAACA-3′, while PA2 has a mismatch (where Py* is substituted by an Im) that should render the binding to be weak to that sequence. Acylation of the γ-turn amino group yields an acetamide (Ac-PA1) with an improved in vivo toxicity profile.

Figure 4.

Recognition of the ARE DNA half-site by PA1. Im/Py pair recognizes G.C, Py/Py pair binds A/T T/A, Py/Im pair recognizes C.G. Figure redrawn from reference.

Figure 5.

Multi-pathway anti-cancer effects of niclosamide. Niclosamide has been shown to 1) affect the STAT, Wnt/β-catenin, and the MAPK pathways, 2) to enhance degradation of AR-V7 and LRP6, and 3) significantly lower key regulators/markers of tumor cell metastasis.

Figure 6.

The effect on the AR-Signaling axis by recently emerged small-molecules that have direct or indirect interaction(s) with the AR N-terminal transactivation domain (TAD) or the DNA binding domain (DBD).