Jun 2026· Accounts of Chemical Research· Vol 59, pp. 2106-2116· 0 citations· 34 references
Medicine
TL;DR
Advances in elucidating the molecular mechanisms underlying AR conformational regulation are summarized and progress in the structure-based design and development of novel AR antagonists are highlighted, highlighting the power of computation-driven approaches in drug discovery.
Abstract
ConspectusProstate cancer (PCa) is the most prevalent malignancy among men worldwide, with its pathogenesis and progression heavily reliant on the sustained activation of the androgen receptor (AR) signaling pathway. The AR, a transcription factor of nuclear receptor superfamily, serves as the most privileged therapeutic target in PCa, as evidenced by the clinical efficacy of first- and second-generation AR antagonists. Current clinically available AR antagonists exclusively target the ligand binding pocket (LBP), suppressing tumor proliferation through competitive inhibition of androgen binding and subsequent blockade of AR signaling transduction. However, their therapeutic utility is invariably limited by acquired resistance mechanisms, including point mutations that alter LBP specificity, AR gene amplification leading to receptor overexpression, and the emergence of constitutively active splice variants that bypass ligand-dependent activation. Thus, the development of novel AR antagonists featuring innovative mechanisms and structural scaffolds is imperative to overcome resistance to antiandrogen therapy. However, the AR exhibits significant structural flexibility, and the lack of antagonist-bound crystal structures has hindered structure-based rational drug design. In this Article, we summarize our advances in elucidating the molecular mechanisms underlying AR conformational regulation and highlight our progress in the structure-based design and development of novel AR antagonists. First, our molecular dynamic (MD) studies collectively elucidate the molecular mechanisms by which the AR ligand binding domain (LBD) regulates its functional states through dynamic conformational changes mediated by distinct allosteric pathways when bound to agonists or antagonists, providing atomic-level insights and structural basis for drug development. Then, we successfully identified structurally diverse lead compounds targeting the LBP through various integrated approaches combining MD simulations, structure-based virtual screening (SBVS), and systematic biological evaluation. These compounds exhibited potent activity against clinically relevant AR mutations F877L, W742C, T878A, and H875Y, demonstrating their potential to overcome mutations-driven resistance. Further, we explored non-LBP mediated strategies for AR antagonism, including: (1) targeting the allosteric binding sites on LBD; (2) identification of novel druggable binding sites; and (3) targeting alternative domains beyond the LBD. As a paradigm-shifting example, we proposed inhibition of AR LBD dimerization as a novel mechanism of action for LBP-targeting AR antagonists. Building upon this insight, we characterized a promising pocket at the dimer interface, designated the Dimerization Interface Pocket (DIP), and developed first-in-class antagonists specifically targeting this site, which exhibit exceptional therapeutic potential. Collectively, these multipronged strategies not only highlight the power of computation-driven approaches in drug discovery but also yield a diverse pipeline of resistance-targeting candidates, directly addressing the unmet clinical need in advanced PCa.
Castration-resistant prostate cancer (CRPC) is lethal because of persistent androgen receptor (AR) signaling, even when patients undergo androgen deprivation therapy. Resistance can arise through intratumoral androgen synthesis, AR overexpression, mutations in the ligand-binding domain, constitutively active splice variants such as AR-V7, and activation of compensatory bypass pathways. Chinese medicine (CM), with its inherent polypharmacology, offers a promising strategy to target multiple AR resistance mechanisms simultaneously. This review summarizes evidence supporting the use of CM-derived compounds, extracts, and formulas to suppress multiple AR mechanisms as a therapeutic strategy against CRPC. It also discusses challenges in clinical translatability, including compositional complexity and bioavailability. CM is a promising approach to overcoming CRPC resistance and warrants standardized formulation development and rigorous clinical validation.
Peiyao Ren, Yuanyang Tian, Boda Guo et al.· Integrative Medicine in Neph...· 0 citations
Androgen receptor (AR) is a therapeutic target for prostate cancer. Despite effective drugging its folded ligand-binding domain (LBD), resistance will develop by mechanisms involving reactivation of AR signaling. These mechanisms include expression of constitutively active AR that lacks LBD such as AR-V7 which fueled the discovery of inhibitors that bind to AR's N-terminal intrinsically disordered transactivation domain (TAD). AR-TAD inhibitors (ARTADIs) are unique due to the paucity of small molecule inhibitors that bind directly to intrinsically disordered TADs, which have historically been considered undruggable. Several ARTADIs have been tested in first-in human clinical trials with acceptable safety and have shown proof-of-concept for the scaffold. Over 20 years we have designed, synthesized and empirically tested over 500 ARTADIs. Leveraging this proprietary platform using cultured prostate cancer cells and multiple xenograft models we demonstrate that subtle changes in the chemical scaffold produce distinct pharmacological outputs that extend beyond binary AR antagonism. Transcriptomic analyses revealed that individual ARTADIs differentially regulate subsets of AR-responsive genes, including both androgen-induced and androgen-repressed programs, resulting in compound-specific remodeling of the AR transcriptome and signaling pathways implicated in tumor progression. These findings support a model of transcriptome-selective pharmacology. Mechanistically, these compounds differentially disrupt interactions between full-length AR or splice-variant AR-V7, and co-regulators, as revealed by rapid immunoprecipitation mass spectrometry of endogenous protein and the proximity ligation assay. This is suggestive that minor alterations in the chemical structure of ARTADIs stabilize distinct AR-TAD conformational ensembles that drive selective cofactor engagement and downstream transcriptional programs. Biophysically, several ARTADIs exhibited picomolar-to-low-nanomolar dissociation constants and covalent binding to cysteine 129. This demonstrates that intrinsically disordered transactivation domains can be targeted with affinities comparable to, or exceeding, those achieved by the LBD inhibitor enzalutamide. In vivo, representative ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. Collectively, these findings support the concept that direct targeting of the intrinsically disordered AR-TAD enables transcriptome-selective pharmacology, providing a mechanistic framework and a novel therapeutic strategy that may complement conventional AR-directed therapies.
Marianne D. Sadar. Direct targeting of the intrinsically disordered transactivation domain of androgen receptor enables transcriptome-selective pharmacology [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA02.
Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as AR-V7. Second, AR-independent or bypass pathways, most notably PI3K/AKT/mTOR, Wnt/β-catenin, MAPK, and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of TP53 and RB1 and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes.
S. Riolo, G. Gallo, A. Cicione et al.· Société Internationale d'Uro...· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 amplification and is associated with early recurrence, metastasis, and poor overall survival. Increasing evidence implicates metabolic dysregulation as a major promoter of TNBC progression, particularly hyperinsulinemia and activation of the PI3K/AKT/mTOR signaling cascade. Novel therapies such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the management of ER-positive breast cancer (BC), leading to significantly improved clinical outcomes, however lack efficacy in TNBC. The PI3K/AKT/mTOR signaling cascade is the most frequently activated pathway in metastatic BC and provides a bypass route that enables continued cell proliferation despite CDK4/6 blockade, thereby driving resistance to CDK4/6 inhibitors and justifying a combined treatment targeting cell cycle and mTOR signaling. We have developed a novel treatment for TNBC based on the biguanide metformin structure, termed JD006, which significantly inhibits TNBC cell growth in vitro and in vivo in a dose-dependent manner and at lower doses than its parental metformin (p<0.01). In syngeneic mouse TNBC models, JD006 reduced TNBC tumor growth and lung metastasis. Transcriptome analysis revealed a decrease in expression of oxidative phosphorylation genes in the lungs of treated mice, and oral administration of JD006 did not produce significant alteration of blood glucose or lactate levels. Mechanistically, JD006 treatment induces AMPK phosphorylation and attenuates mTORC1 signaling, evidenced by reduced phosphorylation of S6 ribosomal protein and 4E-BP1. Seahorse assays reveal marked inhibition of oxidative phosphorylation and ATP synthase along with a compensatory increase in glycolytic ATP production. Furthermore, JD006 induces apoptosis through the intrinsic pathway by reducing levels of Bcl-2, Bcl-xL, and Bax. In addition, JD006 decreases cyclin D1 expression, thereby functionally intersecting with CDK4/6-mediated control of Rb phosphorylation and the G1–S cell cycle transition. When combined with selective CDK4/6 inhibitors, JD006 produces additive and synergistic antiproliferative effects in vitro, accompanied by enhanced suppression of Rb phosphorylation compared with either agent alone. In vivo, combination therapy significantly reduced tumor growth relative to single-agent alone in orthotopic TNBC mouse xenografts (p<0.01). Collectively, these findings support a therapeutic paradigm in which simultaneous disruption of mitochondrial bioenergetics, apoptosis promotion and cyclin D–CDK4/6–Rb signaling exploits a key metabolic–cell cycle dependency in TNBC. This work not only elucidates previously underappreciated mechanisms of biguanide-mediated metabolic reprogramming but also provides a strong preclinical rationale for combining next-generation biguanides with CDK4/6 inhibitors as a novel strategy for this high-risk breast cancer subtype.
Julie Liu, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Linsey Stiles, Nalo Hamilton, Michael E. Jung, Richard J. Pietras, Diana Marquez-Garban. Multi-pathway inhibition and synergistic anticancer activity of novel biguanides in triple negative breast cancer models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A077.
Julie Liu, Mario Morales Martinez, Eduardo Mauricio Gonzalez et al.· Clinical Cancer Research· 0 citations
Multiple phase 3 studies have shown that early use of androgen receptor (AR) pathway inhibitors (ARPIs) results in marked improvement in overall survival for men with metastatic androgen pathway modulation-sensitive (APMS) prostate cancer (formerly castration-sensitive prostate cancer). However, resistance to these agents and progression to androgen pathway modulation-resistant (APMR) prostate cancer (formerly castration-resistant prostate cancer) inevitably occurs. As such, patients previously treated with an ARPI for APMS prostate cancer have inherently more resistant disease. In spite of this, AR still remains a relevant therapeutic target in most patients with APMR prostate cancer and several novel therapies targeting both AR-dependent and -independent mechanisms of resistance are under clinical development. These include hormonal therapies that appear effective in the setting of well-characterized ARPI resistance mutations (e.g. AR ligand binding domain mutations), and include non-ligand binding domain inhibitors, AR degraders and next-generation extra-gonadal androgen biosynthesis inhibitors. This review will also discuss combinatorial approaches utilizing ARPIs and newer agents designed to suppress key resistance mechanisms (e.g. epigenetic therapies) and emerging data on the use of supraphysiological testosterone to both exert an antitumor effect and “re-sensitize” APMR prostate cancer to downstream ARPIs. Herein, we summarize the next wave of AR-directed therapies being developed for advanced prostate cancer, with a focus on agents being evaluated in ongoing clinical trials.
Gabrielle Paras, M. Schweizer· Urologic oncology· 1 citation
Metastatic castration-resistant prostate cancer (mCRPC) remains driven by persistent androgen receptor (AR) signaling, including ligand-independent activity mediated by AR splice variants such as AR-V7. These variants are not addressed by current therapies, highlighting the need for novel approaches to suppress AR signaling.Here, we describe a first-in-class strategy targeting the RNA-binding protein NONO using TF-Scan, a mass spectrometry–based functional proteomics platform that quantifies chromatin-associated protein networks in live cells. NONO is involved in the alternative splicing of a subset of mRNAs, including AR, enabling a unique opportunity to target all AR isoforms, including mutants and splice variants.Using TF-Scan, we identified a covalent small-molecule series that selectively engages NONO at C145 in prostate cancer cells. Mechanistically, these compounds act as RNA molecular glues, modulating the association of NONO to AR pre-mRNA and altering its processing. This results in reduced accumulation of AR mRNA isoforms and decreased levels of both full-length AR and AR-V7 proteins.TF-Scan profiling demonstrates a concomitant reduction in chromatin-bound AR and HOXB13, confirming pathway suppression at the functional level. Through iterative medicinal chemistry guided by proteome-wide selectivity and functional readouts, we optimized compounds with sub-micromolar potency and robust anti-proliferative activity in AR-dependent models. Importantly, using an inactive enantiomer and RNA-seq, we demonstrate that our compounds are highly selective, perturbing a restricted subset of genes, including AR.Together, these findings establish NONO as a tractable target in mCRPC and introduce RNA molecular gluing as a novel modality to suppress AR signaling. More broadly, this work highlights the power of mass spectrometry–based functional proteomics to enable drug discovery against transcriptional regulators and RNA-processing proteins.
Brian McEllin, Daniele Canzani, Lindsay Pino, David Moebius, Gaelle Mercenne, Alexander Federation. Targeting NONO as a therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B096.
Brian McEllin, D. Canzani, Lindsay K. Pino et al.· Clinical Cancer Research· 0 citations
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