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| Status |
Public on Jul 28, 2021 |
| Title |
Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Polyadenylated RNA profiles of LNCaP cells treated with dihydrotestosterone (DHT) plus either DMSO (Control), Enzalutamide, or VPC-220010, in three biological replicates, obtained using BGISeq500 platform.
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| Contributor(s) |
Cavga A, Lack NA |
| Citation(s) |
34298700 |
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| Submission date |
Apr 26, 2021 |
| Last update date |
Jul 28, 2021 |
| Contact name |
Ayse Derya Cavga |
| E-mail(s) |
acavga13@ku.edu.tr
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| Organization name |
Koc University
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| Street address |
Rumelifeneri Yolu, Sariyer
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| City |
Istanbul |
| ZIP/Postal code |
34450 |
| Country |
Turkey |
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| Platforms (1) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA725196 |
| SRA |
SRP316376 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE173331_DESeq2Results_NTD_220010.xlsx |
5.4 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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