Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer
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ABSTRACT:
PROVIDER: PRJNA725196 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14325815.fastq.gz | Fastqsanger.gz | |||
| SRR14325816.fastq.gz | Fastqsanger.gz | |||
| SRR14325817.fastq.gz | Fastqsanger.gz | |||
| SRR14325818.fastq.gz | Fastqsanger.gz | |||
| SRR14325819.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance occurs when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or when constitutively active splice variants lacking the androgen binding domain entirely (e.g. ARV7) is expressed. In this study, we are reporting the discovery of novel AR-NTD covalent inhibitor 1‐chloro‐3‐[(5‐([(2S)‐3‐chloro‐2‐hydroxypropyl]amino)naphthalen‐1‐yl)amino]propan‐2‐ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and its known coactivators and interactors, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule AR-NTD inhibitor for the treatment of CRPC.
2021-07-28 | GSE173331 | GEO
Project description:The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signalling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. While previous studies have focused on ligand-dependent AR signalling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that the AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a distinct gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal. LNCaP, C4-2B, or 22RV1 cells were cultured in hormone-free media for 3 days and then treated with ethanol vehicle or DHT (10nM) for 4h or 16h prior to ChIP-seq or RNA-seq assays. For siRNA transfection, cells were transfected with AR siRNA or control siRNA for 3 days prior to RNA-seq assays.
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Project description:Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors
2015-10-01 | GSE62645 | GEO
Project description:The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signalling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. While previous studies have focused on ligand-dependent AR signalling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that the AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a distinct gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal.
2012-10-02 | GSE40050 | GEO
Project description:Clinical resistance such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) restrict the second-generation antiandrogens benefit in patients with castration-resistant prostate cancer (CRPC). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. In this study, based on rational drug design, we discovered and identified a bifunctional small molecule Z15 as a potent AR antagonist and AR selective degrader. Z15 could directly bind to the AR ligand-binding domain (LBD) and inhibited DHT-induced AR nuclear translocation. Furthermore, Z15 promoted AR degradation through the proteasome pathway. As a result, our in vitro and in vivo studies showed Z15 efficiently suppressed AR and AR mutant transcription activity, downregulated mRNA and protein levels of AR target genes, as well as overcame AR LBD mutations, AR amplification, and ARVs-induced resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
2023-02-02 | PXD035721 | Pride
Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.
2013-02-15 | GSE44319 | GEO
Project description:Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.
2023-07-31 | GSE232849 | GEO
Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity. Tumor Harvest. When tumor size reached approximately 1.5 cm in diameter (6-8 weeks after injection), and the serum PSA was greater than 50 ng/ml, animals were surgically castrated under methoxyfluorane anesthesia and monitored for PSA levels for several weeks. Animals were sacrificed by carbon dioxide asphyxiation when tumors were harvested at several points along the PSA curve (pre-castrate (11), regressing (6), nadir (10), recurring (6) and castration resistant (12). Tumor segments were placed in RNALater (Qiagen) and frozen immediately at -80M-BM-0C.weeks. Tumors were harvested at several points along the PSA curve. The epithelial:stromal ratio is consistent within this tumor model and varies 10% between tumors, as assessed by immunohistochemistry of cytokeratin 14 (epithelium) and vimentin (stroma).
2013-02-15 | E-GEOD-44319 | biostudies-arrayexpress
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Nuclear receptor (NR)-mediated transcription is a dynamic process that is regulated by the binding of distinct ligands that induce conformational changes in the NR. These molecular alterations lead to the recruitment of unique cofactors (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of AR is necessary for maximal androgen-mediated prostate cancer cell growth and migration. Furthermore, this polyproline domain is necessary for the expression of a subset of AR-target genes, but is dispensable for classical AR-mediated gene transcription. Using T7 phage display, we subsequently identified a novel AR-interacting protein, SH3YL1, whose interaction with AR is dependent upon this polyproline domain. Like the AR polyproline domain, SH3YL1 was required for maximal androgen-mediated cell growth and migration. Microarray analysis revealed that SH3YL1 also regulated a subset of AR-modulated genes. Correspondingly, we identified ubinuclein1 (UBN1), a key member of a histone H3.3 chaperone complex, as a transcriptional target of AR/SH3YL1. Moreover, UBN1 was necessary for maximal androgen-mediated proliferation and migration. Collectively, our data link a specific surface located within AR’s N-terminus to the recruitment of a novel cofactor, SH3YL1, which is required for the androgen-mediated expression of UBN1. Importantly, this signaling network was important for both androgen-mediated prostate cancer cell growth and migration. This work is significant because it could aid in the development of selective androgen receptor modulators (SARMs) and have therapeutic implications for AR-driven diseases.
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