Dual-mechanism estrogen receptor inhibitors

Jian Min, Jerome C Nwachukwu, Charles K Min, Jacqline W Njeri, Sathish Srinivasan, Erumbi S Rangarajan, Charles C Nettles, Valeria Sanabria Guillen, Yvonne Ziegler, Shunchao Yan, Kathryn E Carlson, Yingwei Hou, Sung Hoon Kim, Scott Novick, Bruce D Pascal, Rene Houtman, Patrick R Griffin, Tina Izard, Benita S Katzenellenbogen, John A KatzenellenbogenKendall W Nettles

Research output: Contribution to journalArticlepeer-review


Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.

Original languageEnglish (US)
Article numbere2101657118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - Aug 31 2021


  • breast cancer
  • X-ray crystallography
  • cancer therapy
  • SERM
  • estrogen receptor
  • Estrogen receptor
  • Cancer therapy
  • Breast cancer

ASJC Scopus subject areas

  • General


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