Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Abstract

Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.

Hydrogen Sulfide Represses Androgen Receptor Transactivation by Targeting at the Second Zinc Finger Module

“…Androgen ablation via surgical (orchiectomy) or medical (antiandrogens) castration as a first-line therapy has been recognized for a longer time (36). Despite all these therapies, prostate cancer cells invariably develop a variety of cellular pathways to survive and proliferate in an androgen-depleted environment, leading to eventually fatal outcome (4,5). Although several hypotheses, including AR gene amplification, AR gene mutations, involvement of coregulators, and ligandindependent activation of AR, have been proposed to contribute to CRPC, further understanding of the molecular mechanisms triggered by AR signaling during CRPC is critical for designing new potential targets against advanced prostate cancer progression (3,36).…”

“…Upon binding with androgens, AR undergoes a conformational change that ultimately leads to its nuclear translocation and controls the transcriptions of a specific set of androgen-responsive genes, such as prostate-specific antigen (PSA), and concomitant tumor progression (2,3). Androgen deprivation therapy has been used for the initial treatment of prostate cancer; however, there is inevitable disease progression from an androgen-dependent state to an aggressive androgen-resistant state, leading to castration-resistant prostate cancer (CRPC) (3,4). The mechanisms underlying the development of CRPC are largely unclear, although AR signaling still plays important roles in CRPC (5).…”

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…The SAR for AF-2 targeting have been extensively studied [124][125][126] , and X-ray structures of AR-LBD in complex with T (PDB: 2AM9), R-bicalutamide (PDB codes: 1Z95 and 4OJB, Figure 14) or hydroxyflutamide (PDB: 2AX6) and other ligands have been resolved [127] . Essentially, the compounds consist of three structural parts: the first part is usually an studies.…”

Untitled

“…The human androgen receptor, a member of the nuclear hormone receptor family, is a liganddependent transcription factor with known significant therapeutic relevance in prostate cancer 3 .Similar to other nuclear receptors, the androgen receptor is organized into three distinct domains: An N-terminal domain, followed by a DNA binding and a C-terminal ligand binding domains 4 .…”

“…In an attempt to overcome resistance to conventional anti-androgens, computational modeling and high throughput screening techniques have been used to identify small molecules that specifically target functional surface sites of the androgen receptor 4 .…”