Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting the N-terminus of the androgen receptor for prostate cancer therapy

ABSTRACT: All current clinically approved androgen deprivation therapies for prostate cancer (PCa) target the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR), although the N-terminal domain (NTD) is the main regulator of AR activity. Targeting the AR NTD directly is a challenge because of its intrinsic disordered nature and the lack of secondary structure and clefts for drugs to bind. Here, we make use of the cochaperone BAG1L that functions through the NTD to develop alternative AR inhibitors. We show that BAG1L binds to a short alpha-helical region of the AR NTD and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by a small molecule 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17) downregulates AR target gene expression and blocks proliferation of AR-positive PCa cells. Targeting a cochaperone as a surrogate to the AR NTD is therefore key to developing novel AR antagonists.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159606 | GEO | 2021/07/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A small molecule BAG1 inhibitor as therapeutic agent for androgen receptor positive prostate cancer

Project description:BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also bind to diverse cellular proteins and control several signaling processes including proteostasis, apoptosis and transcription. The largest BAG1 isoform (BAG1L) controls the activity of the androgen receptor and is upregulated in prostate cancer. Here, we show that BAG1L binds to the AR N-terminal domain (NTD) and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by targeting the BAG domain with a small molecule, 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), downregulates AR target gene expression and blocks proliferation of AR-positive prostate cancer cells. A4B17 also inhibits tumor development in mouse xenograft models under castration conditions. A4B17 is therefore a BAG1 inhibitor with unique properties to inhibit prostate cancer growth.

2022-05-05 | GSE182278 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-seq C-terminal mutant]

Project description:Targeting the activation function-1 (AF-1) at the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the BAG domain of the cochaperone Bag-1L. Mutations in this domain or loss of Bag-1L abrogates AR signaling and reduces PCa growth. Correspondingly, Bag-1L protein levels increase with progression of primary prostate tumors to castration-resistant PCa, correlating inversely with patient response to abiraterone therapy. Intriguingly, BAG domain residues important for its interaction with the AR AF-1 overlap a potentially druggable pocket of this protein. Bag-1L is therefore a putative therapeutic target for the inhibition of AR AF-1 activity.

2017-08-23 | GSE102183 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [ChIP-Seq]

2017-08-23 | GSE89938 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-Seq KO]

2017-08-23 | GSE89917 | GEO

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

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

LNCaP prostate cancer cell lines overexpressing wild-type or GARRPR-mutant Bag-1L

Project description:The BF-3 pocket of the androgen receptor (AR) has been identified as an allosteric modulator of the transactivation function of the AR. We now demonstrate that a duplicated GARRPR motif at the N-terminus of the cochaperone Bag-1L functions through this BF-3 domain. Amino acid exchanges in these two motifs impair binding of Bag-1L to the AR but increase the androgen-dependent activation of a subset of AR-target genes. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the receptor. LNCaP cells stably expressing the empty vector construct (=control), or wild-type or N-terminal GARRPR mutant Bag-1L were cultured under hormone-starvation conditions for 72 h and then treated with vehicle or 10 nM DHT for 4 h. Biological triplicate samples were analyzed for each cell line.

2014-02-18 | E-GEOD-51524 | biostudies-arrayexpress

LNCaP prostate cancer cell lines overexpressing wild-type or GARRPR-mutant Bag-1L

2014-02-18 | GSE51524 | GEO

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: kinetic analysis after DHT treatment

Project description:Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq dataset and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity, and that this repressive function could be pathologically abrogated by AR variants in PCA.

2022-10-13 | PXD029520 | Pride

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: BioID analysis

2022-10-14 | PXD029454 | Pride

Inhibiting Androgen Receptor Splice Variants with Cysteine-Selective Irreversible Covalent Inhibitors to Treat Prostate Cancer

Project description:Prostate cancer (PCa) affects over 250,000 men in the US. Androgen Receptor (AR) signaling inhibitors are the mainstay therapeutics for PCa. Advanced PCa that expresses AR splice variants (AR-SVs) does not respond to current therapeutic strategies. In this manuscript, we uncovered the physicochemical properties of the intrinsically-disordered transactivation domain of AR and AR-SV and developed novel AR irreversible covalent antagonists (SARICA) to the transactivation domain for the treatment of advanced PCa. SARICAs were also used to identify a potential binding region in the AR and AR-SV transactivation domain.

2022-12-31 | GSE215335 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data