ArticleThe Journal of biological chemistry2016
Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02606123 (A Phase 1/2 Open-Label Study to Assess the Safety, Pharmacokinetics, and Anti-Tumor Activity of Oral EPI-506 in Patients With Metastatic Castration-Resistant Prostate Cancer), which is not on this map. Cited by 34 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
A Phase 1/2 Open-Label Study to Assess the Safety, Pharmacokinetics, and Anti-Tumor Activity of Oral EPI-506 in Patients With Metastatic Castration-Resistant Prostate Cancer
Who cites it
34 citing papers in PubMed, 58 citations in OpenAlex.
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- Androgen receptor inhibitors in treating prostate cancer.Asian journal of andrology · 2025Review
- Inhibitors of the transactivation domain of androgen receptor as a therapy for prostate cancer.Steroids · 2024Review
- Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice.Molecular oncology · 2024Article
- 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
- Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain.ACS medicinal chemistry letters · 2023Article
- A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer.Frontiers in oncology · 2023Review
- Constitutively Active Androgen Receptor in Hepatocellular Carcinoma.International journal of molecular sciences · 2022Review
- Article
- Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors.Advances in experimental medicine and biology · 2022Article
- AR Structural Variants and Prostate Cancer.Advances in experimental medicine and biology · 2022Article
- Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer.Journal of natural products · 2021Article
- Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor.Communications biology · 2021Article
- An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.International journal of molecular sciences · 2021Review
- Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on.Cancers · 2021Review
- Therapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer.Asian journal of urology · 2020Review
- Biologically active marine natural products and their molecular targets discovered using a chemical genetics approach.Natural product reports · 2020Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity. Inhibitors of AR AF-1 would potentially block most AR mechanisms of resistance including constitutively active AR splice variants that lack the ligand-binding domain. Here we provide evidence that sintokamide A (SINT1) binds AR AF-1 region to specifically inhibit transactivation of AR NTD. Consistent with SINT1 targeting AR AF-1, it attenuated transcriptional activities of both full-length AR and constitutively active AR splice variants, which correlated with inhibition of growth of enzalutamide-resistant prostate cancer cells expressing AR splice variants. In vivo, SINT1 caused regression of CRPC xenografts and reduced expression of prostate-specific antigen, a gene transcriptionally regulated by AR. Inhibition of AR activity by SINT1 was additive to EPI-002, a known AR AF-1 inhibitor that is in clinical trials (NCT02606123). This implies that SINT1 binds to a site on AF-1 that is unique from EPI. Consistent with this suggestion, these two compounds showed differences in blocking AR interaction with STAT3. This work provides evidence that the intrinsically disordered NTD of AR is druggable and that SINT1 analogs may provide a novel scaffold for drug development for the treatment of prostate cancer or other diseases of the AR axis.
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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.