Nonsteroidal Bivalent
Estrogen Ligands: An Application
of the Bivalent Concept to the Estrogen Receptor
Posted on 2013-04-19 - 00:00
The estrogen receptor (ER) is a hormone-regulated transcription
factor that binds, as a dimer, to estrogens and to specific DNA sequences.
To explore at a fundamental level the geometric and topological features
of bivalent-ligand binding to the ER dimer, dimeric ER crystal structures
were used to rationally design nonsteroidal bivalent estrogen ligands.
Guided by this structure-based ligand design, we prepared two series
of bivalent ligands (agonists and antagonists) tethered by flexible
spacers of varying lengths (7–47 Å) and evaluated their
ER-binding affinities for the two ER subtypes and their biological
activities in cell lines. Bivalent ligands based on the agonist diethylstilbestrol
(DES) proved to be poor candidates, but bivalent ligands based on
the antagonist hydroxytamoxifen (OHT) were well suited for intensive
study. Binding affinities of the OHT-based bivalent ligands were related
to spacer length in a distinctive fashion, reaching two maximum values
at 14 and 29 Å in both ER subtypes. These results demonstrate
that the bivalent concept can operate in determining ER-ligand binding
affinity and suggest that two distinct modes operate for the binding
of bivalent estrogen ligands to the ER dimers, an intermolecular as well as an intramolecular mode. Our insights,
particularly the possibility of intramolecular bivalent binding on
a single ER monomer, may provide an alternative strategy for preparing
more selective and active ER antagonists for endocrine therapy of
breast cancer.
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Shan, Min; Carlson, Kathryn
E.; Bujotzek, Alexander; Wellner, Anja; Gust, Ronald; Weber, Marcus; et al. (2016). Nonsteroidal Bivalent
Estrogen Ligands: An Application
of the Bivalent Concept to the Estrogen Receptor. ACS Publications. Collection. https://doi.org/10.1021/cb3006243
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AUTHORS (8)
MS
Min Shan
KC
Kathryn
E. Carlson
AB
Alexander Bujotzek
AW
Anja Wellner
RG
Ronald Gust
MW
Marcus Weber
JK
John A. Katzenellenbogen
RH
Rainer Haag