EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer

Lucas J. Brand, Margaret E. Olson, Preethi Ravindranathan, Hong Guo, Aaron M. Kempema, Timothy E. Andrews, Xiaoli Chen, Ganesh V. Raj, Daniel A. Harki, Scott M. Dehm

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARγ). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR NTD, and reduced AR expression. EPI-001 inhibited growth of AR-positive and ARnegative PCa cell lines, with the highest sensitivity observed in LNCaP cells. Overall, this study provides new mechanistic insights to the chemical biology of EPI-001, and raises key issues regarding the use of covalent inhibitors of the intrinsically unstructured AR NTD.

Original languageEnglish (US)
Pages (from-to)3811-3824
Number of pages14
JournalOncotarget
Volume6
Issue number6
DOIs
StatePublished - 2015

Keywords

  • Androgen Receptor
  • Bisphenol A Diglycidyl Ether
  • EPI-001
  • Peroxisome Proliferator-Activated Receptor-gamma
  • Prostate Cancer

ASJC Scopus subject areas

  • Oncology

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