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

doi:10.1021/acschembio.6b00182

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

Medical Sciences

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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 language	English
Pages (from-to)	2499-2505
Number of pages	6
Journal	ACS Chemical Biology
Volume	11
Issue number	9
Early online date	29 Jun 2016
DOIs	https://doi.org/10.1021/acschembio.6b00182
Publication status	Published - 16 Sept 2016

Bibliographical note

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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Accepted Manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acschembio.6b00182
Accepted author manuscript, 1.04 MBLicence: Unspecified

Iain McEwan
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Moll, E. D., Fenwick, R. B., Phang, C. T. W., Buzon, V., Szulc, E., De La Fuente, A., Escobedo, A., Garcia, J., Bertoncini, C. W., Estebanez-Perpina, E., McEwan, I. J., 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, 11(9), 2499-2505. https://doi.org/10.1021/acschembio.6b00182

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

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

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.",

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

note = "ACKNOWLEDGEMENTS We thank J. M. Valverde (IRB) as well as the NMR facilities of the University of Barcelona (CCiT UB) and the Instituto de Qu{\'i}mica F{\'i}sica 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), Marat{\'o} 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 Ram{\'o}n 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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AU - Fenwick, R. Bryn

AU - Phang, Christopher T.W.

AU - Buzon, Victor

AU - Szulc, Elzbieta

AU - De La Fuente, Alex

AU - Escobedo, Albert

AU - Garcia, Jesus

AU - Bertoncini, Carlos W.

AU - Estebanez-Perpina, Eva

AU - McEwan, Iain J.

AU - Riera, Antoni

AU - Salvatella, Xavier

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)

PY - 2016/9/16

Y1 - 2016/9/16

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.

AB - 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.

U2 - 10.1021/acschembio.6b00182

DO - 10.1021/acschembio.6b00182

M3 - Article

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VL - 11

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EP - 2505

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 9

ER -

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

Abstract

Bibliographical note

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