ArticleProceedings of the National Academy of Sciences of the United States of America2023
Inhibiting androgen receptor splice variants with cysteine-selective irreversible covalent inhibitors to treat prostate cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 42 citations in OpenAlex.
- Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19Nature medicine · 2024Trial
- Targeting the Androgen Receptor and Associated Cofactors in Prostate Cancer: Novel Approaches and Future Perspectives.International journal of molecular sciences · 2026Review
- Small molecules modulate the biomolecular condensates and liquid‒liquid phase separation.Acta pharmaceutica Sinica. B · 2026Review
- Conformational transition of a polycationic hinge domain contributes to DNA binding.Biophysical chemistry · 2026Article
- Condensatopathies as a mechanistic framework for disease and integrated theranostic intervention.Theranostics · 2026Review
- Identification of CAND1 as a DNA-dependent protein kinase-regulated coactivator of androgen receptor and the ARv7 splice variant.PloS one · 2026Article
- Endocrine Examples of Phase Separation in Biology.Endocrinology · 2025Review
- Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer.Oncogene · 2025Review
- Ensemble Docking for Intrinsically Disordered Proteins.Journal of chemical information and modeling · 2025Article
- Covalent Adducts Formed by the Androgen Receptor Transactivation Domain and Small Molecule Drugs Remain Disordered.Journal of chemical information and modeling · 2025Article
- Conformational modulation of intrinsically disordered transactivation domains for cancer therapy.PNAS nexus · 2025Review
- The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression and abiraterone resistance.British journal of cancer · 2025Article
- Ensemble docking for intrinsically disordered proteins.bioRxiv : the preprint server for biology · 2025Article
- Androgen Signaling in Prostate Cancer: When a Friend Turns Foe.Endocrine, metabolic & immune disorders drug targets · 2025Review
- The androgen receptor amino-terminal domain: structure, function and therapeutic potential.Endocrine oncology (Bristol, England) · 2025Review
- Liquid-liquid phase separation in cell physiology and cancer biology: recent advances and therapeutic implications.Frontiers in oncology · 2025Review
- Liquid-liquid phase separation: an emerging perspective on the tumorigenesis, progression, and treatment of tumors.Frontiers in immunology · 2025Review
- Inhibitors of the transactivation domain of androgen receptor as a therapy for prostate cancer.Steroids · 2024Review
- Review
- Biomolecular condensates and disease pathogenesis.Science China. Life sciences · 2024Review
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
Abstract
Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.