Journal
CANCERS
Volume 13, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/cancers13143488
Keywords
castration resistant prostate cancer; androgen receptor inhibitor; N-terminal domain; small molecule inhibitor; computer-aided drug design; AR splice variants
Categories
Funding
- Canadian Institutes of Health Research [272111, 390757]
Ask authors/readers for more resources
This study reports the discovery of a novel AR-NTD covalent inhibitor VPC-220010, which selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines by disrupting interactions between AR and known coactivators and coregulatory proteins. VPC-220010 shows promise as a small molecule that can be further optimized into an effective AR-NTD inhibitor for the treatment of CRPC.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available