title: Full antagonism of the estrogen receptor without a prototypical ligand side chain.
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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Jerome C
authors.identifier: 0000-0003-4313-9187
authors.initials: JC
authors.lastname: Nwachukwu
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Nelson E
authors.initials: NE
authors.lastname: Bruno
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Dharmarajan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Devrishi
authors.initials: D
authors.lastname: Goswami
authors.affiliation: Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois, USA.
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Novick
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cavett
authors.affiliation: 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.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois, USA.
authors.forename: Nittaya
authors.initials: N
authors.lastname: Boonmuen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois, USA.
authors.forename: Yuechao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, Illinois, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois, USA.
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois, USA.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, Illinois, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011960:Receptors, Estrogen