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

Content Provider	MDPI
Author	Ban, Fuqiang Leblanc, Eric Cavga, Ayse Huang, Chia-Chi Flory, Mark Zhang, Fan Chang, Matthew Morin, Hélène Lallous, Nada Singh, Kriti Gleave, Martin Mohammed, Hisham Rennie, Paul Lack, Nathan Cherkasov, Artem
Copyright Year	2021
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.
Starting Page	3488
e-ISSN	20726694
DOI	10.3390/cancers13143488
Journal	Cancers
Issue Number	14
Volume Number	13
Language	English
Publisher	MDPI
Publisher Date	2021-07-12
Access Restriction	Open
Subject Keyword	Cancers Oncology Castration Resistant Prostate Cancer Androgen Receptor Inhibitor N-terminal Domain Small Molecule Inhibitor Computer-aided Drug Design Ar Splice Variants
Content Type	Text
Resource Type	Article

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