EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

Eva De Moll, R. Bryn Fenwick, Christopher T.W. Phang, Victor Buzon, Elzbieta Szulc, Alex De La Fuente, Albert Escobedo, Jesus Garcia, Carlos W. Bertoncini, Eva Estebanez-Perpina, Iain J. McEwan, Antoni Riera, Xavier Salvatella

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Abstract

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.
Original languageEnglish
Pages (from-to)2499-2505
Number of pages6
JournalACS Chemical Biology
Volume11
Issue number9
Early online date29 Jun 2016
DOIs
Publication statusPublished - 16 Sep 2016

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Castration
Androgen Receptors
Transcriptional Activation
Androgens
Prostatic Neoplasms
Androgen Receptor Antagonists
Poisons
Cytoplasmic and Nuclear Receptors
Refractory materials
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
EPI 001
Therapeutics

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Moll, E. D., Fenwick, R. B., Phang, C. T. W., Buzon, V., Szulc, E., De La Fuente, A., ... Salvatella, X. (2016). EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor. ACS Chemical Biology, 11(9), 2499-2505. https://doi.org/10.1021/acschembio.6b00182

EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor. / Moll, Eva De; Fenwick, R. Bryn; Phang, Christopher T.W.; Buzon, Victor; Szulc, Elzbieta; De La Fuente, Alex; Escobedo, Albert; Garcia, Jesus; Bertoncini, Carlos W.; Estebanez-Perpina, Eva ; McEwan, Iain J.; Riera, Antoni; Salvatella, Xavier .

In: ACS Chemical Biology, Vol. 11, No. 9, 16.09.2016, p. 2499-2505.

Research output: Contribution to journalArticle

Moll, ED, Fenwick, RB, Phang, CTW, Buzon, V, Szulc, E, De La Fuente, A, Escobedo, A, Garcia, J, Bertoncini, CW, Estebanez-Perpina, E, McEwan, IJ, Riera, A & Salvatella, X 2016, 'EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor' ACS Chemical Biology, vol. 11, no. 9, pp. 2499-2505. https://doi.org/10.1021/acschembio.6b00182
Moll, Eva De ; Fenwick, R. Bryn ; Phang, Christopher T.W. ; Buzon, Victor ; Szulc, Elzbieta ; De La Fuente, Alex ; Escobedo, Albert ; Garcia, Jesus ; Bertoncini, Carlos W. ; Estebanez-Perpina, Eva ; McEwan, Iain J. ; Riera, Antoni ; Salvatella, Xavier . / EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor. In: ACS Chemical Biology. 2016 ; Vol. 11, No. 9. pp. 2499-2505.
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abstract = "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.",
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AU - Szulc, Elzbieta

AU - De La Fuente, Alex

AU - Escobedo, Albert

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AU - McEwan, Iain J.

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N1 - ACKNOWLEDGEMENTS We thank J. M. Valverde (IRB) as well as the NMR facilities of the University of Barcelona (CCiT UB) and the Instituto de Química Física Rocasolano (IQFR, CSIC) for their assistance in, respectively, protein production and NMR. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (Fellowship to E.D.M. and CancerTec grants to X.S.) MICINN (CTQ2009-08850 to X.S.), MINECO (BIO2012-31043 to X.S.; CTQ2014-56361-P to A.R), Marató de TV3 (102030 to X.S. and 102031 to E.E.P) the COFUND programme of the European Commission (C.T.W.P., A. R. and X.S.), the European Research Council (CONCERT, contract number 648201, to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.) the Serra Hunter Programme (E.E.P.) and AGAUR (SGR-2014-56RR14 to E.E.P). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)

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N2 - 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.

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