| Reference | 1. ACS Chem Biol. 2016 Sep 16;11(9):2499-505. doi: 10.1021/acschembio.6b00182. Epub
2016 Jul 14. <br />
EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets
Transactivation Unit 5 of the Androgen Receptor. <br />
De Mol E(1), Fenwick RB(1), Phang CT(1), Buzón V(2), Szulc E(1), de la Fuente
A(1), Escobedo A(1), García J(1), Bertoncini CW(1), Estébanez-Perpiñá E(2),
McEwan IJ(3), Riera A(1)(4), Salvatella X(1)(5). <br />
Author information: <br />
(1)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute
of Science and Technology , Baldiri Reixac 10, 08028 Barcelona, Spain.
(2)Departament de Bioquímica i Biología Molecular, and Institute of Biomedicine,
University of Barcelona (IBUB) , Baldiri Reixac 10, 08028 Barcelona, Spain.
(3)Institute of Medical Sciences, School of Medicine, Medical Sciences and
Nutrition, University of Aberdeen , IMS Building, Foresterhill, Aberdeen AB25
2ZD, Scotland , United Kingdom.
(4)Departament de Química Orgànica, Universitat de Barcelona , Martí i Franqués
1-11, 08028 Barcelona, Spain.
(5)ICREA, Passeig Lluís Companys 23 , 08010 Barcelona, Spain. <br />
Castration-resistant prostate cancer is the lethal condition suffered by prostate
cancer patients that become refractory to androgen deprivation therapy. EPI-001
is a recently identified compound active against this condition that modulates
the activity of the androgen receptor, a nuclear receptor that is essential for
disease progression. The mechanism by which this compound exerts its inhibitory
activity is however not yet fully understood. Here we show, by using high
resolution solution nuclear magnetic resonance spectroscopy, that EPI-001
selectively interacts with a partially folded region of the transactivation
domain of the androgen receptor, known as transactivation unit 5, that is key for
the ability of prostate cells to proliferate in the absence of androgens, a
distinctive feature of castration-resistant prostate cancer. Our results can
contribute to the development of more potent and less toxic novel androgen
receptor antagonists for treating this disease. <br />
2. Oncotarget. 2015 Feb 28;6(6):3811-24. <br />
EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator
with inhibitory effects on androgen receptor expression and activity in prostate
cancer. <br />
Brand LJ(1)(2), Olson ME(3), Ravindranathan P(4), Guo H(5), Kempema AM(3),
Andrews TE(3), Chen X(5), Raj GV(4), Harki DA(3), Dehm SM(2)(6). <br />
Author information: <br />
(1)Graduate Program in Microbiology, Immunology, and Cancer Biology, University
of Minnesota, Minneapolis, MN, USA.
(2)Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
(3)Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN,
USA.
(4)Department of Urology, University of Texas Southwestern Medical Center,
Dallas, Texas, USA.
(5)Department of Food Science and Nutrition, University of Minnesota,
Minneapolis, MN, USA.
(6)Department of Laboratory Medicine and Pathology, University of Minnesota,
Minneapolis, MN, USA. <br />
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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