title: EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.
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 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.
authors: Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors: Lucas J
authors: LJ
authors: Brand
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors: Margaret E
authors: ME
authors: Olson
authors: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Preethi
authors: P
authors: Ravindranathan
authors: Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA.
authors: Hong
authors: H
authors: Guo
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors: Aaron M
authors: AM
authors: Kempema
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors: Timothy E
authors: TE
authors: Andrews
authors: Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA.
authors: Xiaoli
authors: X
authors: Chen
authors: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Ganesh V
authors: GV
authors: Raj
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors: Daniel A
authors: DA
authors: Harki
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors: Scott M
authors: SM
authors: Dehm
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002728:Chlorohydrins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D001559:Benzhydryl Compounds; D002728:Chlorohydrins; C551471:EPI 001; D011944:Receptors, Androgen