Development of an androgen receptor inhibitor targeting the n-terminal domain of androgen receptor for treatment of castration resistant prostate cancer

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

Research output: Contribution to journalArticlepeer-review

Abstract

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-ter-minal 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.

Original languageEnglish (US)
Article number3488
JournalCancers
Volume13
Issue number14
DOIs
StatePublished - Jul 2 2021

Keywords

  • Androgen receptor inhibitor
  • AR splice variants
  • Castration resistant prostate cancer
  • Computer-aided drug design
  • N-terminal domain
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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