Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

LaFrate, Andrew L.; Carlson, Kathryn E.; Katzenellenbogen, John A.

doi:10.1016/j.bmc.2009.04.016

Cited by 30 publications

(29 citation statements)

References 36 publications

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“…Since then several other groups have published bivalent or dimeric steroid syntheses using a variety of linkers [27, 28, 29, 30], but these papers focused on design, synthesis and/or binding, with little to no characterization of relative efficacy, potency or specificity. More recently, the Katzenellenbogen laboratory, publishers of the original manuscript on the synthesis of bivalent hexestrols, extended these studies with bivalent estrogen designs that displayed variable estrogen receptor binding affinities that correlated with linker length [31]. These estrogen dimers were evaluated comprehensively with respect to linker composition, tether length and receptor binding, but did not evaluate biological activity.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and functional analysis of novel bivalent estrogens

et al. 2010

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The steroid hormone estrogen plays a critical role in female development and homeostasis. Estrogen mediates its effects through binding and activation of specific estrogen receptors alpha (ERα) and beta (ERβ), members of the steroid/nuclear receptor family of ligand-induced transcription factors. Due to their intimate roles in genomic and nongenomic signaling pathways, these hormones and their receptors have been also implicated in the pathologies of a variety of cancers and metabolic disorders, and have been the target of large therapeutic development efforts. The binding of estrogen to its respective receptors initiates a cascade of events that include receptor dimerization, nuclear localization, DNA binding and recruitment of co-regulatory protein complexes. In this manuscript, we investigate the potential for manipulating steroid receptor gene expression activity through the development of bivalent steroid hormones that are predicted to facilitate hormone receptor dimerization events. Data are presented for the development and testing of novel estrogen dimers, linked through their C-17 moiety, that can activate estrogen receptor alpha (ERα)-mediated transcription events with efficacy and potency equal to or greater than that of ERα’s cognate ligand, 17β-estradiol. These bivalent estrogen structures open the door to the development of a variety of steroid therapeutics that could dramatically impact future drug development in this area.

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Section: Resultsmentioning

confidence: 99%

Synthesis and functional analysis of novel bivalent estrogens

et al. 2010

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“…For comparison, we modeled the structure of a bivalent steroidal ligand published by LaFrate et al [22], where an EG5 spacer connects two E 2 s modified at the 17a position. Our data (not shown) suggests that this bivalent ligand also suffers from a drop in end-to-end distances (measured at the C17 positions) to a mean value distinctly below 10 Å .…”

Section: Resultsmentioning

confidence: 99%

“…During the last two decades, several bivalent ER ligands, composed of two individual ligands linked by flexible tethers, have been designed and synthesized [4,10,22]. In 2010, Wendlandt et al showed the biological activity of synthetic bivalent estrogen dimers linked by aliphatic spacers to be higher than that of 17b-estradiol [33].…”

Section: Bivalent Inhibition Of Estrogen Receptormentioning

confidence: 99%

Towards a rational spacer design for bivalent inhibition of estrogen receptor

Bujotzek

Shan

Haag

et al. 2011

J Comput Aided Mol Des

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Estrogen receptors are known drug targets that have been linked to several kinds of cancer. The structure of the estrogen receptor ligand binding domain is available and reveals a homodimeric layout. In order to improve the binding affinity of known estrogen receptor inhibitors, bivalent compounds have been developed that consist of two individual ligands linked by flexible tethers serving as spacers. So far, binding affinities of the bivalent compounds do not surpass their monovalent counterparts. In this article, we focus our attention on the molecular spacers that are used to connect the individual ligands to form bivalent compounds, and describe their thermodynamic contribution during the ligand binding process. We use computational methods to predict structural and entropic parameters of different spacer structures. We find that flexible spacers introduce a number of effects that may interfere with ligand binding and possibly can be connected to the low binding affinities that have been reported in binding assays. Based on these findings, we try to provide guidelines for the design of novel molecular spacers.

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“…Another very ancient receptor is the estrogen receptor (ER) (5), and John Katzenellenbogen (University of Illinois, Urbana) pointed out that compounds of diverse structure having a phenolic back-bone can function as estrogens (6). Although many compounds can activate ERs, tissue selectivity is conferred by tissue-specific activation of different effector gene networks.…”

Section: Evolution Of Nr Specificitymentioning

confidence: 99%

Chemical Approaches to Nuclear Receptors in MetabolismA report on the workshop “Chemical Approaches to Nuclear Receptors and Metabolism,” sponsored by National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA, 16 to 17 April 2009.

Margolis¹,

Moore²,

Willson³

et al. 2009

Sci. Signal.

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The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, “Chemical Approaches to Nuclear Receptors and Metabolism,” in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics.

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Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

Cited by 30 publications

References 36 publications

Synthesis and functional analysis of novel bivalent estrogens

Synthesis and functional analysis of novel bivalent estrogens

Towards a rational spacer design for bivalent inhibition of estrogen receptor

Chemical Approaches to Nuclear Receptors in MetabolismA report on the workshop “Chemical Approaches to Nuclear Receptors and Metabolism,” sponsored by National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA, 16 to 17 April 2009.

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