Development of heterodimeric estrogen receptor alpha antagonists to target simultaneously the ligand and coactivator binding site.
breast cancer
coactivator binding site
endocrine resistance
estrogen receptor
subtype selectivity
Journal
Archiv der Pharmazie
ISSN: 1521-4184
Titre abrégé: Arch Pharm (Weinheim)
Pays: Germany
ID NLM: 0330167
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
revised:
07
04
2023
received:
09
12
2022
accepted:
12
04
2023
medline:
6
7
2023
pubmed:
13
5
2023
entrez:
13
5
2023
Statut:
ppublish
Résumé
One-third of breast cancer patients will develop recurrent cancer within 15 years of endocrine treatment. Notably, tumor growth in a hormone-refractory state still relies on the interaction between estrogen receptor alpha (ERα) and upregulated coactivators. Herein, we suggest that simultaneous targeting of the primary ligand binding site (LBS) and the coactivator binding site (CABS) at ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. We synthesized two series of compounds that connect the LBS-binder (E)-3-{4-[8-fluoro-4-(4-hydroxyphenyl)-2,3-dihydrobenzo[b]oxepin-5-yl]phenyl}acrylic acid 8 with the coactivator binding site inhibitors (CBIs) 4,6-bis(isobutyl(methyl)amino)pyrimidine or 3-(5-methoxy-1H-benzo[d]imidazol-2-yl)propanoic acid via covalent linkage. The most active benzoxepine-pyrimidine conjugate 31 showed strong inhibition of estradiol-induced transactivation (IC
Identifiants
pubmed: 37173820
doi: 10.1002/ardp.202200638
doi:
Substances chimiques
acrylic acid
J94PBK7X8S
Estrogen Receptor alpha
0
Estrogen Receptor beta
0
Ligands
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2200638Informations de copyright
© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.
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