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

Sathish Srinivasan, Jerome C. Nwachukwu, Nelson E. Bruno, Venkatasubramanian Dharmarajan, Devrishi Goswami, Irida Kastrati, Scott Novick, Jason Nowak, Valerie Cavett, Hai Bing Zhou, Nittaya Boonmuen, Yuechao Zhao, Jian Min, Jonna Frasor, Benita S. Katzenellenbogen, Patrick R. Griffin, John A. Katzenellenbogen, Kendall W. Nettles

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)111-118
Number of pages8
JournalNature chemical biology
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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