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EPI-002 accelerates ligand dissociation from androgen receptor by disrupting N-terminus to C-terminus interaction Ding, Rick
Abstract
Constitutively active splice variants of androgen receptor (AR) lacking the ligand-binding domain (LBD) are linked to the development and progression of castration-resistant prostate cancer (CRPC). Recent studies suggest a constitutively active splice variant, ARv⁵⁶⁷es, is capable of interacting with full-length AR, stabilizing and enhancing its ligand-dependent activities despite castrate levels of circulating androgen. EPI-001, an AR antagonist targeting the Nterminus domain (NTD) prevents N-terminus to C-terminus (N/C) interaction of AR, which is essential for AR antiparallel dimer formation. The ligand-dependent N/C interactions slow the dissociation of ligand from the LBD. Here we examine the effect of EPI-002, the most potent stereoisomer of EPI-001, on ARv⁵⁶⁷es complexed with full-length AR and test the hypothesis that EPI-002 will cause ligand to dissociate more quickly because it blocks N/C interaction. The aim of this study is two-fold as we first examined the effects of ARv⁵⁶⁷es on the dissociation rate of the full-length receptor. Then, we examined the effect of EPI-002 on the ligand dissociation rate of full-length AR with and without the presence of ARv⁵⁶⁷es. We have demonstrated that EPI-002 did not affect binding affinity of wild-type full-length AR nor the time for it to reach binding equilibrium. EPI-002 accelerated the ligand dissociation rate of wild-type full-length AR possibly by disrupting N/C interaction. Co-expression of ectopic ARv567es and wild-type full-length AR at 50:50 ratios did not alter the ligand dissociation rate of wild-type full-length AR but attenuated the effect of EPI-002. However, EPI-002 had minimal effect on the ligand dissociation rate of endogenous AR in LNCaP prostate cancer cells, consistent with the lack of effect when AR has a mutation in the LBD (T877A) that enhances the N/C interaction and slows the ligand dissociation rate compared to the wild-type AR. Together these data begin to reveal 1) the unique mechanisms of splice variant ARv⁵⁶⁷es on the dissociation rate of full-length AR; and 2) the effect of an AR NTD inhibitor on the dissociation rate of full-length AR with and without the presence of splice variants.
Item Metadata
Title |
EPI-002 accelerates ligand dissociation from androgen receptor by disrupting N-terminus to C-terminus interaction
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2013
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Description |
Constitutively active splice variants of androgen receptor (AR) lacking the ligand-binding
domain (LBD) are linked to the development and progression of castration-resistant prostate
cancer (CRPC). Recent studies suggest a constitutively active splice variant, ARv⁵⁶⁷es, is capable
of interacting with full-length AR, stabilizing and enhancing its ligand-dependent activities
despite castrate levels of circulating androgen. EPI-001, an AR antagonist targeting the Nterminus
domain (NTD) prevents N-terminus to C-terminus (N/C) interaction of AR, which is
essential for AR antiparallel dimer formation. The ligand-dependent N/C interactions slow the
dissociation of ligand from the LBD. Here we examine the effect of EPI-002, the most potent
stereoisomer of EPI-001, on ARv⁵⁶⁷es complexed with full-length AR and test the hypothesis that
EPI-002 will cause ligand to dissociate more quickly because it blocks N/C interaction. The aim
of this study is two-fold as we first examined the effects of ARv⁵⁶⁷es on the dissociation rate of
the full-length receptor. Then, we examined the effect of EPI-002 on the ligand dissociation rate
of full-length AR with and without the presence of ARv⁵⁶⁷es.
We have demonstrated that EPI-002 did not affect binding affinity of wild-type full-length AR
nor the time for it to reach binding equilibrium. EPI-002 accelerated the ligand dissociation rate
of wild-type full-length AR possibly by disrupting N/C interaction. Co-expression of ectopic
ARv567es and wild-type full-length AR at 50:50 ratios did not alter the ligand dissociation rate of
wild-type full-length AR but attenuated the effect of EPI-002. However, EPI-002 had minimal
effect on the ligand dissociation rate of endogenous AR in LNCaP prostate cancer cells,
consistent with the lack of effect when AR has a mutation in the LBD (T877A) that enhances the N/C interaction and slows the ligand dissociation rate compared to the wild-type AR. Together
these data begin to reveal 1) the unique mechanisms of splice variant ARv⁵⁶⁷es on the
dissociation rate of full-length AR; and 2) the effect of an AR NTD inhibitor on the dissociation
rate of full-length AR with and without the presence of splice variants.
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Genre | |
Type | |
Language |
eng
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Date Available |
2015-10-31
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0103358
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2013-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International