ArticleInternational journal of cancer2019
Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models.
Article in International journal of cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Induction of cellular senescence by androgen receptor agonist or antagonist is mediated via two novel common DYRK1A-DREAM and cyclin G2 signaling pathways in castration-resistant prostate cancer.Journal of advanced research · 2026Article
- Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance.Journal of the National Cancer Center · 2026Review
- Pathological complete response to perioperative treatment with darolutamide plus ADT in locally advanced prostate cancer without PTEN or RB1 loss: a case report.Frontiers in pharmacology · 2026Article
- Harnessing Single-Cell RNA-Seq for Computational Drug Repurposing in Cancer Immunotherapy.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Review
- Real-world effectiveness of darolutamide in metastatic castration-resistant prostate cancer.Endocrine-related cancer · 2025Article
- Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity.Cell · 2025Article
- UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis.Molecular oncology · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Let's Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer.International journal of molecular sciences · 2023Review
- Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment.International journal of molecular sciences · 2023Review
- Comparative Proteomic and Transcriptomic Analysis of the Impact of Androgen Stimulation and Darolutamide Inhibition.Cancers · 2022Article
- Biotransformation novel advances - 2021 year in review.Drug metabolism reviews · 2022Review
- Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.Assay and drug development technologies · 2022Article
- Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer.Journal of medicinal chemistry · 2021Article
- Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Resistance to second-generation androgen receptor antagonists in prostate cancer.Nature reviews. Urology · 2021Review
- Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on.Cancers · 2021Review
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Authors and funding
8 authors.
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Abstract
Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell-based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto-darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand-binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen-dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down-regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC-4 cell line-derived xenograft and of the KuCaP-1 patient-derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.
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