ArticleMolecular oncology2020
Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer.
Article in Molecular oncology, 2020. 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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Who cites it
30 citing papers in PubMed, 46 citations in OpenAlex.
- Drugging the intrinsically disordered transactivation domain of androgen receptor.Signal transduction and targeted therapy · 2026Article
- Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer.Journal of the National Cancer Center · 2026Review
- Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.Frontiers in oncology · 2026Review
- Identification of CAND1 as a DNA-dependent protein kinase-regulated coactivator of androgen receptor and the ARv7 splice variant.PloS one · 2026Article
- Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective.Journal of cell communication and signaling · 2025Article
- Covalent Adducts Formed by the Androgen Receptor Transactivation Domain and Small Molecule Drugs Remain Disordered.Journal of chemical information and modeling · 2025Article
- Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates.BMC biology · 2025Review
- Conformational modulation of intrinsically disordered transactivation domains for cancer therapy.PNAS nexus · 2025Review
- Looking beyond the ER, PR, and HER2: what's new in the ARsenal for combating breast cancer?Reproductive biology and endocrinology : RB&E · 2025Review
- The androgen receptor amino-terminal domain: structure, function and therapeutic potential.Endocrine oncology (Bristol, England) · 2025Review
- Prognostic role of Androgen Receptor splice variant 7 (AR-V7) in the pathogenesis of breast cancer.BMC cancer · 2024Article
- Inhibitors of the transactivation domain of androgen receptor as a therapy for prostate cancer.Steroids · 2024Review
- Androgen Receptor-Interacting Proteins in Prostate Cancer Development and Therapy Resistance.The American journal of pathology · 2024Review
- Treatments Targeting the Androgen Receptor and Its Splice Variants in Breast Cancer.International journal of molecular sciences · 2024Review
- N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review.Frontiers in pharmacology · 2024Review
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Pinostilbene inhibits full-length and splice variant of androgen receptor in prostate cancer.Scientific reports · 2023Article
- Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI-001 in in vitro Models of Prostate Cancer Drug Resistance.ChemMedChem · 2023Article
- A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer.Frontiers in oncology · 2023Review
- Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states.Nature communications · 2022Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Resistance of castration-resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD. Here, we evaluated the antitumor effect of a next-generation analog of ralaniten (EPI-7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR-V7 that were resistant to enzalutamide. EPI-7170 had 8-9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR-V7 and expression of its target genes. Knockdown of AR-V7 restored sensitivity to enzalutamide, indicating a role for AR-V7 in the mechanism of resistance. EPI-7170 inhibited expression of genes transcriptionally regulated by full-length AR and AR-V7. A combination of EPI-7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide-resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.
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