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Nat Chem Biol. 2017 Jan;13(1):111-118. doi: 10.1038/nchembio.2236. Epub 2016 Nov 21.

Full antagonism of the estrogen receptor without a prototypical ligand side chain.

Author information

1
Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
2
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
3
Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois, USA.
4
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, State Key Laboratory of Virology, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.
5
Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois, USA.
6
Department of Chemistry, University of Illinois, Urbana, Illinois, USA.

Abstract

Resistance to endocrine therapies remains a major clinical problem for the treatment of 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.

PMID:
27870835
PMCID:
PMC5161551
DOI:
10.1038/nchembio.2236
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

statement The authors declare no competing financial interests.

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