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Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer

Castration resistant prostate cancer (CRPC) continues to be androgen receptor (AR) driven. Inhibition of AR signaling in CRPC could be advanced using state-of-the-art biophysical and biochemical techniques. Structural characterization of AR and its complexes by cryo-electron microscopy would advance...

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Autores principales: Asangani, Irfan, Blair, Ian A., Van Duyne, Gregory, Hilser, Vincent J., Moiseenkova-Bell, Vera, Plymate, Stephen, Sprenger, Cynthia, Wand, A. Joshua, Penning, Trevor M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949100/
https://www.ncbi.nlm.nih.gov/pubmed/33384381
http://dx.doi.org/10.1074/jbc.REV120.012411
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author Asangani, Irfan
Blair, Ian A.
Van Duyne, Gregory
Hilser, Vincent J.
Moiseenkova-Bell, Vera
Plymate, Stephen
Sprenger, Cynthia
Wand, A. Joshua
Penning, Trevor M.
author_facet Asangani, Irfan
Blair, Ian A.
Van Duyne, Gregory
Hilser, Vincent J.
Moiseenkova-Bell, Vera
Plymate, Stephen
Sprenger, Cynthia
Wand, A. Joshua
Penning, Trevor M.
author_sort Asangani, Irfan
collection PubMed
description Castration resistant prostate cancer (CRPC) continues to be androgen receptor (AR) driven. Inhibition of AR signaling in CRPC could be advanced using state-of-the-art biophysical and biochemical techniques. Structural characterization of AR and its complexes by cryo-electron microscopy would advance the development of N-terminal domain (NTD) and ligand-binding domain (LBD) antagonists. The structural basis of AR function is unlikely to be determined by any single structure due to the intrinsic disorder of its NTD, which not only interacts with coregulators but likely accounts for the constitutive activity of AR-splice variants (SV), which lack the LBD and emerge in CRPC. Using different AR constructs lacking the LBD, their effects on protein folding, DNA binding, and transcriptional activity could reveal how interdomain coupling explains the activity of AR-SVs. The AR also interacts with coregulators that promote chromatin looping. Elucidating the mechanisms involved can identify vulnerabilities to treat CRPC, which do not involve targeting the AR. Phosphorylation of the AR coactivator MED-1 by CDK7 is one mechanism that can be blocked by the use of CDK7 inhibitors. CRPC gains resistance to AR signaling inhibitors (ARSI). Drug resistance may involve AR-SVs, but their role requires their reliable quantification by SILAC–mass spectrometry during disease progression. ARSI drug resistance also occurs by intratumoral androgen biosynthesis catalyzed by AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase), which is unique in that its acts as a coactivator of AR. Novel bifunctional inhibitors that competitively inhibit AKR1C3 and block its coactivator function could be developed using reverse-micelle NMR and fragment-based drug discovery.
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spelling pubmed-79491002021-03-19 Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer Asangani, Irfan Blair, Ian A. Van Duyne, Gregory Hilser, Vincent J. Moiseenkova-Bell, Vera Plymate, Stephen Sprenger, Cynthia Wand, A. Joshua Penning, Trevor M. J Biol Chem JBC Reviews Castration resistant prostate cancer (CRPC) continues to be androgen receptor (AR) driven. Inhibition of AR signaling in CRPC could be advanced using state-of-the-art biophysical and biochemical techniques. Structural characterization of AR and its complexes by cryo-electron microscopy would advance the development of N-terminal domain (NTD) and ligand-binding domain (LBD) antagonists. The structural basis of AR function is unlikely to be determined by any single structure due to the intrinsic disorder of its NTD, which not only interacts with coregulators but likely accounts for the constitutive activity of AR-splice variants (SV), which lack the LBD and emerge in CRPC. Using different AR constructs lacking the LBD, their effects on protein folding, DNA binding, and transcriptional activity could reveal how interdomain coupling explains the activity of AR-SVs. The AR also interacts with coregulators that promote chromatin looping. Elucidating the mechanisms involved can identify vulnerabilities to treat CRPC, which do not involve targeting the AR. Phosphorylation of the AR coactivator MED-1 by CDK7 is one mechanism that can be blocked by the use of CDK7 inhibitors. CRPC gains resistance to AR signaling inhibitors (ARSI). Drug resistance may involve AR-SVs, but their role requires their reliable quantification by SILAC–mass spectrometry during disease progression. ARSI drug resistance also occurs by intratumoral androgen biosynthesis catalyzed by AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase), which is unique in that its acts as a coactivator of AR. Novel bifunctional inhibitors that competitively inhibit AKR1C3 and block its coactivator function could be developed using reverse-micelle NMR and fragment-based drug discovery. American Society for Biochemistry and Molecular Biology 2021-01-09 /pmc/articles/PMC7949100/ /pubmed/33384381 http://dx.doi.org/10.1074/jbc.REV120.012411 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle JBC Reviews
Asangani, Irfan
Blair, Ian A.
Van Duyne, Gregory
Hilser, Vincent J.
Moiseenkova-Bell, Vera
Plymate, Stephen
Sprenger, Cynthia
Wand, A. Joshua
Penning, Trevor M.
Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title_full Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title_fullStr Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title_full_unstemmed Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title_short Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
title_sort using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer
topic JBC Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949100/
https://www.ncbi.nlm.nih.gov/pubmed/33384381
http://dx.doi.org/10.1074/jbc.REV120.012411
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