Development of novel inhibitors targeting ...
Document type :
Article dans une revue scientifique: Article original
DOI :
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Title :
Development of novel inhibitors targeting the d-box of the dna binding domain of androgen receptor
Author(s) :
Radaeva, Mariia [Auteur]
Ban, Fuqiang [Auteur]
Zhang, Fan [Auteur]
Leblanc, Eric [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Lallous, Nada [Auteur]
Rennie, Paul S. [Auteur]
Gleave, Martin E. [Auteur]
Cherkasov, Artem [Auteur]
Ban, Fuqiang [Auteur]
Zhang, Fan [Auteur]
Leblanc, Eric [Auteur]

Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Lallous, Nada [Auteur]
Rennie, Paul S. [Auteur]
Gleave, Martin E. [Auteur]
Cherkasov, Artem [Auteur]
Journal title :
International Journal of Molecular Sciences
Abbreviated title :
Int. J. Mol. Sci.
Volume number :
22
Pages :
2493
Publication date :
2021-03-02
ISSN :
1422-0067
Keyword(s) :
androgen receptor
prostate cancer
small-molecule inhibitors
computer-aided drug discovery
dimerization
prostate cancer
small-molecule inhibitors
computer-aided drug discovery
dimerization
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor ...
Show more >The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.Show less >
Show more >The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
INSERM
Université de Lille
Université de Lille
Submission date :
2022-06-15T14:00:05Z
2023-03-08T10:02:32Z
2023-03-08T10:02:32Z
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