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.
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Female
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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Receptors, Estrogen / antagonists & inhibitors*
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Receptors, Estrogen / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Ligands
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Receptors, Estrogen
Associated data
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PubChem-Substance/318480741
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PubChem-Substance/318480742
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PubChem-Substance/318480743
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PubChem-Substance/318480744
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PubChem-Substance/318480745
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PubChem-Substance/318480746
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PubChem-Substance/318480747
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PubChem-Substance/318480748
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PubChem-Substance/318480749
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PubChem-Substance/318480750
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PubChem-Substance/318480751
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PubChem-Substance/318480752
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PubChem-Substance/318480753
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PubChem-Substance/318480754
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PubChem-Substance/318480755
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PubChem-Substance/318480756
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PubChem-Substance/318480757
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PubChem-Substance/318480758
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PubChem-Substance/318480733
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PubChem-Substance/318480734
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PubChem-Substance/318480735
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PubChem-Substance/318480736
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PubChem-Substance/318480737
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PubChem-Substance/318480738
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PubChem-Substance/318480739
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PubChem-Substance/318480740