EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer
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Lucas J. Brand1,2, Margaret E. Olson3, Preethi Ravindranathan4, Hong Guo5, Aaron M. Kempema3, Timothy E. Andrews3, Xiaoli Chen5, Ganesh V. Raj4, Daniel A. Harki3, Scott M. Dehm2,6
1Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN, USA
2Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
3Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA
4Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
5Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA
6Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Scott M. Dehm, e-mail: [email protected]
Keywords: EPI-001, Bisphenol A Diglycidyl Ether, Androgen Receptor, Prostate Cancer, Peroxisome Proliferator-Activated Receptor-gamma
Received: December 12, 2014 Accepted: December 14, 2014 Published: January 12, 2015
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 AR-negative 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.
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