Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells

Elgehama, Ahmed; Sun, Lijun; Yu, Biao; Guo, Wenjie; Xu, Qiang

doi:10.1007/s10637-020-01050-w

Cited by 6 publications

(6 citation statements)

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“…SBF1 has been reported to act as a SET domain–dependent regulator involved in epigenetic regulatory mechanisms of growth and differentiation ( Cui et al, 1998 ). It inhibits proliferation, induces apoptosis, and causes cell cycle arrest through the inhibition of the insulin-like growth factor 1–proliferating cell nuclear antigen pathway ( Elgehama et al, 2021 ). Our results reflect the underlying functioning pathways in which placental eccDNA is involved.…”

Section: Discussionmentioning

confidence: 99%

“…The clean reads were then aligned to all chromosomes and mitochondrial DNA using the bwa-mem2 program (Vasimuddin et al, 2019). We tested several algorithms for eccDNA identification [Circle-Map (Prada-Luengo et al, 2019), ecc_finder (Zhang et al, 2021a), AmpliconArchitect (Deshpande et al, 2019), and two scripts from Circle_finder (Kumar et al, 2017)], and preliminarily validated the results by visualization with the IGV (Robinson et al, 2011). The bwa-mem-samblaster.sh Circle_finder pipeline was deemed optimal and modified for our analysis.…”

Section: Identification Of Eccdna From Multiple Sourcesmentioning

confidence: 99%

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Integrative profiling of extrachromosomal circular DNA in placenta and maternal plasma provides insights into the biology of fetal growth restriction and reveals potential biomarkers

et al. 2023

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Introduction: Fetal growth restriction (FGR) is a placenta-mediated pregnancy complication that predisposes fetuses to perinatal complications. Maternal plasma cell-free DNA harbors DNA originating from placental trophoblasts, which is promising for the prenatal diagnosis and prediction of pregnancy complications. Extrachromosomal circular DNA (eccDNA) is emerging as an ideal biomarker and target for several diseases.Methods: We utilized eccDNA sequencing and bioinformatic pipeline to investigate the characteristics and associations of eccDNA in placenta and maternal plasma, the role of placental eccDNA in the pathogenesis of FGR, and potential plasma eccDNA biomarkers of FGR.Results: Using our bioinformatics pipelines, we identified multi-chromosomal-fragment and single-fragment eccDNA in placenta, but almost exclusively single-fragment eccDNA in maternal plasma. Relative to that in plasma, eccDNA in placenta was larger and substantially more abundant in exons, untranslated regions, promoters, repetitive elements [short interspersed nuclear elements (SINEs)/Alu, SINEs/mammalian-wide interspersed repeats, long terminal repeats/endogenous retrovirus-like elements, and single recognition particle RNA], and transcription factor binding motifs. Placental multi-chromosomal-fragment eccDNA was enriched in confident enhancer regions predicted to pertain to genes in apoptosis, energy, cell growth, and autophagy pathways. Placental eccDNA–associated genes whose abundance differed between the FGR and control groups were associated with immunity-related gene ontology (GO) terms. The combined analysis of plasma and placental eccDNA–associated genes in the FGR and control groups led to the identification of potential biomarkers that were assigned to the GO terms of the epigenetic regulation of gene expression and nutrient-related processes, respectively.Conclusion: Together, our results highlight links between placenta functions and multi-chromosomal-fragment and single-fragment eccDNA. The integrative analysis of placental and plasma eccDNA confirmed the potential of these molecules as disease-specific biomarkers of FGR.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Eccdna From Multiple Sourcesmentioning

confidence: 99%

Integrative profiling of extrachromosomal circular DNA in placenta and maternal plasma provides insights into the biology of fetal growth restriction and reveals potential biomarkers

et al. 2023

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“…As a result, AR-targeted therapies focusing on the N-terminal domain or DBD of AR have become a subject of intense interest as a potentially promising strategy to overcome AR heterogeneity in prostate cancer. Several N-terminal inhibitors and DBD inhibitors, such as EPI-7386 and SBF-1 have been reported in preclinical studies with promising ability to overcome many known mechanisms of resistance to existing hormonal therapies [131][132][133][134]. The highly selective N-terminal domain inhibitor EPI-7386 is currently in phase 1 and phase 1/2 clinical trials to evaluate the safety, tolerability, and preliminary efficacy of EPI-7386 alone and in combination with enzalutamide in mCRPC (NCT05075577 and NCT04421222).…”

Section: Strategies To Overcome Resistance To Ar Antagonists Developm...mentioning

confidence: 99%

“…The highly selective N-terminal domain inhibitor EPI-7386 is currently in phase 1 and phase 1/2 clinical trials to evaluate the safety, tolerability, and preliminary efficacy of EPI-7386 alone and in combination with enzalutamide in mCRPC (NCT05075577 and NCT04421222). Another recent study has found that the wellcharacterized antitumor agent SBF-1 can selectively bind to the AR-DBD and block the transcription of AR target genes, and has been proven to repress prostate cancer growth both in vitro and in vivo [134]. Beyond targeting alternative AR domains, another strategy to overcome resistance conferred by point mutations in the LBD is the structure-based design of novel AR antagonists to specifically disrupt LBD dimerization, as AR transactivation potential requires LBD-mediated homodimer formation, regardless of the presence or absence of LBD point mutations [135].…”

Section: Strategies To Overcome Resistance To Ar Antagonists Developm...mentioning

confidence: 99%

“…Mechanisms and preclinical/clinical evidence AR DBD inhibitors AR binding to the DNA via its DBD is an essential step in the regulation of gene transcription by both full-length and variant forms of AR [163]. AR DBD inhibitors can effectively inhibit the activity of truncated ARVs and repress PCa growth in vitro and in vivo [129,134,164].…”

Section: Agents/technologiesmentioning

confidence: 99%

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Second generation androgen receptor antagonists and challenges in prostate cancer treatment

et al. 2022

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Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

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Viscosalactone B, a natural LSD1 inhibitor, inhibits proliferation in vitro and in vivo against prostate cancer cells

Yan

Zhang

et al. 2023

Invest New Drugs

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Lysine speci c demethylase 1 (LSD1) has been a promising target to treat prostate cancer, and discovery of the novel LSD1 inhibitor has great clinical signi cance. In this work, viscosalactone B was rst identi ed as a novel LSD1 inhibitor. Viscosalactone B isolated from Withania Somnifera displayed the antiproliferative activity against PC3, DU145, C42B, PC3/MDVR, DU145/MDVR and C42B/MDVR cells with IC 50 values of 1.17, 0.72, 3.86, 2.06, 0.96 and 1.15 µM, respectively. It was a selective LSD1 inhibitor with an IC 50 value of 970.27 nM and concentration-dependently induced the signi cant accumulation of LSD1 substrates H3K9me1, H3K9me2 and H3K4me1 against DU145 cells. According to docking studies, it formed hydrogen bonds with Thr11, Lys14 and Arg8. Importantly, it displayed the potent antitumor e cacy in vivo and exhibited no obvious cytotoxicity on the major organs of nude mice. Therefore, viscosalactone B as a novel LSD1 inhibitor is a potential candidate to treat prostate cancer.

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Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells

Cited by 6 publications

References 70 publications

Integrative profiling of extrachromosomal circular DNA in placenta and maternal plasma provides insights into the biology of fetal growth restriction and reveals potential biomarkers

Integrative profiling of extrachromosomal circular DNA in placenta and maternal plasma provides insights into the biology of fetal growth restriction and reveals potential biomarkers

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

Viscosalactone B, a natural LSD1 inhibitor, inhibits proliferation in vitro and in vivo against prostate cancer cells

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