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Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain
Resistance to endocrine therapies remains a significant clinical problem for estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand serie...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161551/ https://www.ncbi.nlm.nih.gov/pubmed/27870835 http://dx.doi.org/10.1038/nchembio.2236 |
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author | Srinivasan, Sathish Nwachukwu, Jerome C. Bruno, Nelson E. Dharmarajan, Venkatasubramanian Goswami, Devrishi Kastrati, Irida Novick, Scott Nowak, Jason Cavett, Valerie Zhou, Hai-Bing Boonmuen, Nittaya Zhao, Yuechao Min, Jian Frasor, Jonna Katzenellenbogen, Benita S. Griffin, Patrick R. Katzenellenbogen, John A. Nettles, Kendall W. |
author_facet | Srinivasan, Sathish Nwachukwu, Jerome C. Bruno, Nelson E. Dharmarajan, Venkatasubramanian Goswami, Devrishi Kastrati, Irida Novick, Scott Nowak, Jason Cavett, Valerie Zhou, Hai-Bing Boonmuen, Nittaya Zhao, Yuechao Min, Jian Frasor, Jonna Katzenellenbogen, Benita S. Griffin, Patrick R. Katzenellenbogen, John A. Nettles, Kendall W. |
author_sort | Srinivasan, Sathish |
collection | PubMed |
description | Resistance to endocrine therapies remains a significant clinical problem for estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity. |
format | Online Article Text |
id | pubmed-5161551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-51615512017-05-21 Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain Srinivasan, Sathish Nwachukwu, Jerome C. Bruno, Nelson E. Dharmarajan, Venkatasubramanian Goswami, Devrishi Kastrati, Irida Novick, Scott Nowak, Jason Cavett, Valerie Zhou, Hai-Bing Boonmuen, Nittaya Zhao, Yuechao Min, Jian Frasor, Jonna Katzenellenbogen, Benita S. Griffin, Patrick R. Katzenellenbogen, John A. Nettles, Kendall W. Nat Chem Biol Article Resistance to endocrine therapies remains a significant clinical problem for estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity. 2016-11-21 2017-01 /pmc/articles/PMC5161551/ /pubmed/27870835 http://dx.doi.org/10.1038/nchembio.2236 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Srinivasan, Sathish Nwachukwu, Jerome C. Bruno, Nelson E. Dharmarajan, Venkatasubramanian Goswami, Devrishi Kastrati, Irida Novick, Scott Nowak, Jason Cavett, Valerie Zhou, Hai-Bing Boonmuen, Nittaya Zhao, Yuechao Min, Jian Frasor, Jonna Katzenellenbogen, Benita S. Griffin, Patrick R. Katzenellenbogen, John A. Nettles, Kendall W. Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title | Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title_full | Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title_fullStr | Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title_full_unstemmed | Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title_short | Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain |
title_sort | full antagonism of the estrogen receptor without a prototypical ligand side chain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161551/ https://www.ncbi.nlm.nih.gov/pubmed/27870835 http://dx.doi.org/10.1038/nchembio.2236 |
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