What are the therapeutic candidates targeting AR?

Androgen Receptor Overview

Structure and Function of Androgen Receptor

The androgen receptor (AR) is a ligand‐dependent transcription factor from the nuclear receptor superfamily. Its protein structure is remarkable in that it is composed of several modular domains: an intrinsically disordered N-terminal domain (NTD), a highly conserved DNA-binding domain (DBD) that contains two zinc finger motifs responsible for recognizing androgen response elements (AREs) in target gene promoters, and a ligand-binding domain (LBD) that not only recognizes endogenous androgens such as testosterone and dihydrotestosterone (DHT) but also serves as the primary binding pocket for many therapeutic agents. The flexibility of the NTD coupled with the rigid conformation of the DBD and LBD provides the receptor with the ability to undergo substantial conformational rearrangements upon ligand binding. For example, when the AR binds DHT, it undergoes structural shifts that favor N/C-terminal interactions and the recruitment of coactivator proteins necessary for transcriptional activation. These structural changes affect AR dimerization, nuclear translocation, DNA binding and eventually the regulation of gene transcription. Such mechanistic attributes have provided a blueprint not only to understand normal androgen signaling but also to design compounds that can block AR function at multiple steps of its activation cascade.

Role of Androgen Receptor in Disease

The AR’s function is central to the physiology of male sexual development and the maintenance of secondary sexual characteristics. However, its activity also plays a crucial role in the pathogenesis of several diseases. Prostate cancer is the prototypical AR‐driven malignancy. In this disease, AR signaling remains essential even in castration‐resistant prostate cancer (CRPC), where upregulation, mutation of the receptor or the emergence of splice variants—particularly those lacking the LBD—is a well‐documented route of therapeutic resistance. In addition to prostate cancer, AR is expressed in a significant fraction of breast cancers, where its role appears to vary with the estrogen receptor (ER) status. AR may have an inhibitory effect in ER‐positive tumors while it may promote tumorigenesis in ER‐negative cancers. In diseases such as androgen insensitivity syndrome (AIS) and in certain neuromuscular disorders, abnormal AR function can have drastic developmental consequences. Moreover, aberrant AR signaling has also been implicated in non‐oncologic conditions including metabolic disorders and even in cardiovascular disease where its modulation might influence smooth muscle cell proliferation. Overall, the pleiotropic effects of AR under physiological and pathological conditions make it an attractive target for therapeutic intervention from multiple angles.

Current Therapeutic Candidates

Approved Drugs Targeting AR

Currently, a number of drugs have received regulatory approval for targeting the androgen receptor or its associated signaling pathways. The best‐known among these are the second‑generation antiandrogens. Enzalutamide, for instance, is a widely approved agent for metastatic castration‐resistant prostate cancer (mCRPC) and acts through several mechanisms that ultimately inhibit AR signaling. Clinical trials demonstrated that enzalutamide binds to the AR with five‑to‑eight times higher affinity than first‑generation agents (such as bicalutamide), inhibits AR nuclear translocation, prevents DNA binding and thereby halts transcription of AR target genes. Apart from enzalutamide, apalutamide and darolutamide are other approved antiandrogens that follow similar inhibitory principles with subtle differences in safety and pharmacologic profiles. Apalutamide, for example, has been recently approved based on evidence from Phase III trials and is used in both metastatic castration‑sensitive and non‑metastatic CRPC settings. Although abiraterone acetate does not directly bind AR, it has been approved as an androgen biosynthesis inhibitor, greatly reducing the levels of endogenous androgens that activate the receptor. Together, these drugs form the backbone of AR‑directed therapy and have moved to become the treatment standard in many prostate cancer settings. Their clinical utility and regulatory approval have been supported by robust data showing improvements in overall survival, progression‑free survival and clinical outcomes.

Mechanism of Action of Current Therapies

Approved drugs targeting the AR primarily function by interfering with different steps in AR signaling. Enzalutamide and its peers function by competitively binding to the ligand‑binding domain (LBD) of the AR. They not only block the binding of endogenous androgens but also inhibit the conformational change necessary for AR dimerization and nuclear import, thus preventing its subsequent interaction with DNA and the transcriptional machinery. This multi‑step inhibition is critical because AR signaling persists even under conditions of androgen depletion. Abiraterone works upstream by inhibiting CYP17A1, an enzyme crucial for androgen biosynthesis in the testes, adrenal glands and even within the tumor microenvironment. By diminishing overall androgen levels, abiraterone indirectly reduces AR activation. The mechanisms employed by these approved compounds—whether directly through receptor blockade or indirectly by reducing ligand availability—highlight the diverse approaches currently used to disrupt AR signaling. In all cases, the goal of the therapy is to attenuate the transcriptional program driven by AR, thereby suppressing disease progression.

Emerging Therapeutic Candidates

Novel Agents in Clinical Trials

Emerging candidates targeting AR have evolved in response to the clinical challenge of resistance that eventually develops against approved agents. One prominent promising approach is the use of Proteolysis Targeting Chimeras (PROTACs) that induce the degradation of AR protein rather than merely inhibiting its activity. ARV‑110 is a PROTAC molecule currently in Phase II clinical trials that degrades the full‑length AR as well as several mutant variants, potentially overcoming the resistance mechanisms associated with persistent AR signaling. In addition to PROTACs, next‑generation inhibitors that target the N‑terminal domain (NTD) of AR have been actively explored. Unlike the LBD, the NTD is less structured and historically has been challenging to drug. However, compounds such as EPI‑7386 have emerged from clinical trial programs as potent inhibitors of the AR NTD, offering the potential to inhibit both full‑length AR and splice variants that lack the LBD. Another candidate advancing clinically is ONCT‑534 (formerly known as GTx‑534), which has demonstrated promising preclinical activity in models that express AR splice variants, a known hurdle in CRPC treatment. Other novel agents include non‑competitive AR inhibitors (such as TRC‑253) that bind to sites distinct from the ligand binding pocket, thereby inhibiting AR activity via alternative mechanisms. These candidates represent a shift toward more flexible targeting strategies that promise to counteract common resistance pathways observed with conventional LBD inhibitors.

Clinical studies in recent years have begun to incorporate these emerging agents in combination regimens, raising the possibility of additive or even synergistic effects when combined with standard antiandrogens or other pathway inhibitors. For instance, combination studies of next‑generation NTD inhibitors with conventional agents are designed to tackle multiple facets of AR signaling simultaneously, potentially delaying or overcoming resistance, as well as improving response durability. Furthermore, early clinical trials have started evaluating the safety and efficacy of these compounds in patient populations that have failed first‑line therapies, with encouraging preliminary results regarding PSA decline and radiological response.

Preclinical Research on AR Inhibitors

On the preclinical front, there is an extensive effort to discover molecules that offer alternative or complementary mechanisms for targeting AR. Researchers are investigating the development of peptide antagonists that interfere with AR protein-protein interactions by mimicking coregulator binding motifs. Such peptides are being designed for higher specificity with the aim of disrupting critical AR-coactivator interactions, which are essential for AR-mediated transcription. In addition, preclinical studies are exploring compounds that disrupt AR dimerization—a process critical for its full transcriptional activity. AR dimerization inhibitors, sometimes called AR DIMs, have been shown in preclinical models to prevent the proper formation of AR homodimers and thereby impair downstream gene expression.

Other promising strategies involve targeting the co-regulators and chromatin modifiers associated with AR. For example, inhibitors of bromodomain and extraterminal (BET) proteins, such as those that disrupt the interaction between BRD4 and AR, have demonstrated the ability to interrupt AR-driven gene transcription in CRPC models. Detailed structure-activity studies in cellular models have shown that increasing electron-withdrawing groups on inhibitor scaffolds can enhance AR inhibitory potency and engender efficient AR degradation. Furthermore, RNA-based therapeutic approaches, including antisense oligonucleotides targeting AR mRNA (such as ISIS‑ARRx), have emerged as a novel strategy to reduce the expression of both full-length AR and its splice variants. These studies in preclinical settings not only help validate promising targets—such as inhibitors directed at changing AR conformation beyond the classical binding pocket—but also expand our understanding of the receptor’s regulatory network and potential vulnerabilities.

Collectively, these emerging preclinical candidates are being developed with a focus on overcoming the limitations of current therapies. Special attention is given to molecules that can neutralize AR splice variants, mitigate transcriptional activity via the NTD, and even employ protein degradation pathways. The integration of structure-based drug design and high-throughput screening has been pivotal in assuring that these new molecules have enhanced specificity and potency compared to earlier compounds.

Challenges and Future Directions

Resistance Mechanisms

A persistent challenge in AR-targeted therapy is the development of resistance. Even the most potent approved drugs eventually encounter resistance via several mechanisms. One major route is the development of AR splice variants (e.g., AR-V7) that lack the LBD and, therefore, evade inhibition by drugs that target the ligand binding pocket. Additionally, point mutations in the LBD may alter drug binding affinity without compromising receptor function, resulting in resistance to antiandrogens such as enzalutamide. Furthermore, upregulation of coactivators and alterations in chromatin structure can re-activate AR-dependent transcription despite ligand blockade. There is also evidence suggesting that additional pathways, including the glucocorticoid receptor (GR) pathway, can cross-compensate when AR signaling is suppressed, thereby posing an additional therapeutic challenge. These resistance mechanisms necessitate the development of agents with novel mechanisms, such as those that target the NTD or induce AR degradation, as well as combination treatment strategies that address multiple axes of resistance simultaneously.

Future Research and Development

Moving forward, future research should focus on designing agents that target the AR signaling pathway in a more comprehensive manner. For instance, achieving complete AR elimination through proteolysis-targeting chimeras (PROTACs) may provide a means to overcome both ligand-dependent and ligand-independent AR signaling. In parallel, the exploration of AR NTD inhibitors that can block activity in splice variants represents another promising avenue. There is also a growing interest in developing combination therapies that target both AR and its co-regulators or other parallel pathways such as PI3K/mTOR. Such combinations could potentially intercept feedback loops that contribute to resistance and may delay the onset of treatment failure.

Beyond small molecules, the use of RNA-based therapies, including antisense oligonucleotides and RNA interference strategies, hold great promise for silencing AR expression at the message level. These approaches, which are being refined in preclinical studies, offer the potential for highly specific targeting of AR and its variant forms without relying solely on structural inhibition at the protein level. Moreover, newer diagnostic tests and biomarkers based on AR pathway activity are under development to better stratify patients and guide combination therapies. An integrated diagnostic approach—not solely focused on AR gene or protein levels but also encompassing downstream coregulator expression—could help in predicting which patients are likely to benefit from specific AR-targeted therapies and monitor emerging resistance.

Another important research direction is the exploration of noncompetitive AR inhibitors that interact with alternative surfaces on the AR molecule (apart from the LBD), which may include the AF-1 region or even allosteric sites that regulate receptor conformation. These molecules could potentially offer a mechanism to counteract the resistance seen with competitive inhibitors. Preclinical studies that employ molecular dynamics simulations and structure-activity relationship analyses are critical to advancing this area of research by identifying key regions on AR that can be exploited pharmacologically.

In summary, while the current therapeutic candidates—including enzalutamide, apalutamide, darolutamide and abiraterone—have transformed the treatment of AR-driven diseases, overt resistance remains a significant clinical hurdle. Emerging candidates such as PROTACs (e.g., ARV-110), NTD inhibitors (e.g., EPI-7386), noncompetitive inhibitors (e.g., TRC-253), and innovative RNA-based therapeutic approaches offer hope for overcoming these challenges. The future of AR-targeted therapy lies in multidisciplinary approaches that combine rational drug design, combination therapies to address multiple resistance mechanisms, and the integration of novel biomarkers to enable personalized therapy.

Conclusion:

In conclusion, the therapeutic candidates targeting the androgen receptor encompass a spectrum of approaches both in clinical use and in development. At the current stage, approved agents such as enzalutamide, apalutamide, darolutamide and abiraterone have provided meaningful benefits by blocking androgen receptor activation through competitive binding at the ligand binding domain or by reducing androgen levels altogether. Their mechanisms of action disable critical steps in AR signaling including ligand binding, nuclear translocation and downstream gene transcription. However, the inevitable emergence of resistance—often through splice variant formation, point mutations or compensatory upregulation of alternative pathways—has propelled vigorous preclinical and clinical research into novel therapeutic agents. Emerging candidates include next-generation PROTACs designed to degrade AR protein, NTD inhibitors like EPI‑7386 that target receptor regions not affected by conventional drug resistance, and noncompetitive inhibitors that engage allosteric receptor sites. Additionally, preclinical studies are expanding our arsenal by exploring peptide antagonists, dimerization inhibitors and RNA-based approaches to fiercely combat AR signaling and overcome therapeutic escape routes. Future research will undoubtedly focus on combination therapies that simultaneously target AR and its interacting pathways, the development of integrated diagnostic tools to predict treatment response, and the continual evolution of next‑generation therapeutics that are designed with resistance mechanisms in mind. Such multidimensional strategies are expected to result in more durable responses and ultimately improve patient outcomes in AR-driven diseases such as prostate and certain breast cancers.

This integrated model—from the well‑characterized structure and function of AR to the current clinical applications and the cutting‑edge emerging therapies—demonstrates the dynamic evolution of AR-targeted treatment. Continued efforts in these areas are critically needed to outpace resistance and provide transformative therapeutic benefits for patients. The future of AR-targeted therapy is bright, with a growing portfolio of innovative agents that promise to usher in the next era of precision oncology for hormone-driven diseases.