Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer
Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/14/3488 |
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| author | Fuqiang Ban Eric Leblanc Ayse Derya Cavga Chia-Chi Flora Huang Mark R. Flory Fan Zhang Matthew E. K. Chang Hélène Morin Nada Lallous Kriti Singh Martin E. Gleave Hisham Mohammed Paul S. Rennie Nathan A. Lack Artem Cherkasov |
| author_facet | Fuqiang Ban Eric Leblanc Ayse Derya Cavga Chia-Chi Flora Huang Mark R. Flory Fan Zhang Matthew E. K. Chang Hélène Morin Nada Lallous Kriti Singh Martin E. Gleave Hisham Mohammed Paul S. Rennie Nathan A. Lack Artem Cherkasov |
| author_sort | Fuqiang Ban |
| collection | DOAJ |
| description | Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a 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 known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC. |
| first_indexed | 2024-03-10T09:44:19Z |
| format | Article |
| id | doaj.art-b30861a94cf94179bf0e9195a44d3858 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:44:19Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b30861a94cf94179bf0e9195a44d38582023-11-22T03:24:03ZengMDPI AGCancers2072-66942021-07-011314348810.3390/cancers13143488Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate CancerFuqiang Ban0Eric Leblanc1Ayse Derya Cavga2Chia-Chi Flora Huang3Mark R. Flory4Fan Zhang5Matthew E. K. Chang6Hélène Morin7Nada Lallous8Kriti Singh9Martin E. Gleave10Hisham Mohammed11Paul S. Rennie12Nathan A. Lack13Artem Cherkasov14Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaSchool of Medicine, Koç University, Rumelifeneri Yolu, 34450 Istanbul, TurkeyVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaKnight Cancer Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098, USAVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaKnight Cancer Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098, USAVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaKnight Cancer Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098, USAVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaProstate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a 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 known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.https://www.mdpi.com/2072-6694/13/14/3488castration resistant prostate cancerandrogen receptor inhibitorN-terminal domainsmall molecule inhibitorcomputer-aided drug designAR splice variants |
| spellingShingle | Fuqiang Ban Eric Leblanc Ayse Derya Cavga Chia-Chi Flora Huang Mark R. Flory Fan Zhang Matthew E. K. Chang Hélène Morin Nada Lallous Kriti Singh Martin E. Gleave Hisham Mohammed Paul S. Rennie Nathan A. Lack Artem Cherkasov Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer Cancers castration resistant prostate cancer androgen receptor inhibitor N-terminal domain small molecule inhibitor computer-aided drug design AR splice variants |
| title | Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| title_full | Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| title_fullStr | Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| title_full_unstemmed | Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| title_short | Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer |
| title_sort | development of an androgen receptor inhibitor targeting the n terminal domain of androgen receptor for treatment of castration resistant prostate cancer |
| topic | castration resistant prostate cancer androgen receptor inhibitor N-terminal domain small molecule inhibitor computer-aided drug design AR splice variants |
| url | https://www.mdpi.com/2072-6694/13/14/3488 |
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