An androgen receptor N-terminal domain antagonist for treating prostate cancer

Jae-Kyung Myung; Carmen A Banuelos; Javier Garcia Fernandez; Nasrin R Mawji; Jun Wang; Amy H Tien; Yu Chi Yang; Iran Tavakoli; Simon Haile; Kate Watt; Iain J McEwan; Stephen Plymate; Raymond J Andersen; Marianne D Sadar

doi:10.1172/JCI66398

An androgen receptor N-terminal domain antagonist for treating prostate cancer

Jae-Kyung Myung, Carmen A Banuelos, Javier Garcia Fernandez, Nasrin R Mawji, Jun Wang, Amy H Tien, Yu Chi Yang, Iran Tavakoli, Simon Haile, Kate Watt, Iain J McEwan, Stephen Plymate, Raymond J Andersen, Marianne D Sadar

Medical Sciences

Research output: Contribution to journal › Article › peer-review

255 Citations (Scopus)

Abstract

Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

Original language	English
Pages (from-to)	2948-2960
Number of pages	13
Journal	The Journal of Clinical Investigation
Volume	123
Issue number	7
Early online date	3 Jun 2012
DOIs	https://doi.org/10.1172/JCI66398
Publication status	Published - 1 Jul 2013

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Myung, J.-K., Banuelos, C. A., Fernandez, J. G., Mawji, N. R., Wang, J., Tien, A. H., Yang, Y. C., Tavakoli, I., Haile, S., Watt, K., McEwan, I. J., Plymate, S., Andersen, R. J., & Sadar, M. D. (2013). An androgen receptor N-terminal domain antagonist for treating prostate cancer. The Journal of Clinical Investigation, 123(7), 2948-2960. https://doi.org/10.1172/JCI66398

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title = "An androgen receptor N-terminal domain antagonist for treating prostate cancer",

abstract = "Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.",

author = "Jae-Kyung Myung and Banuelos, {Carmen A} and Fernandez, {Javier Garcia} and Mawji, {Nasrin R} and Jun Wang and Tien, {Amy H} and Yang, {Yu Chi} and Iran Tavakoli and Simon Haile and Kate Watt and McEwan, {Iain J} and Stephen Plymate and Andersen, {Raymond J} and Sadar, {Marianne D}",

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AU - Myung, Jae-Kyung

AU - Banuelos, Carmen A

AU - Fernandez, Javier Garcia

AU - Mawji, Nasrin R

AU - Wang, Jun

AU - Tien, Amy H

AU - Yang, Yu Chi

AU - Tavakoli, Iran

AU - Haile, Simon

AU - Watt, Kate

AU - McEwan, Iain J

AU - Plymate, Stephen

AU - Andersen, Raymond J

AU - Sadar, Marianne D

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AB - Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

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DO - 10.1172/JCI66398

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SP - 2948

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JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

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ER -

An androgen receptor N-terminal domain antagonist for treating prostate cancer

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