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

  • A Corrigendum to this article was published on 17 May 2017
  • An Erratum to this article was published on 17 May 2017


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.

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Figure 1: Overview of the ligand-dependent modulation of ERα activity.
Figure 2: OBHS-N analogs exhibit growth-inhibitory and anti-inflammatory effects.
Figure 3: Modulation of ERα signaling by OBHS-N analogs in cells in vitro and in the mouse uterus in vivo. (a–e) Dotted lines represent values for 10 nM E2 (black), 1 μM 4-OHT (blue) and 1 μM fulvestrant (Fulv, red).
Figure 4: Ligand-dependent proteasomal degradation of ERα.
Figure 5: Structural basis for full antagonism of ERα by OBHS-N analogs.
Figure 6: Antagonism of ERα-Y537S.

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  • 17 March 2017

    In the version of this article initially published, Figure 1 was missing the ring designation letters, the substituent designation (R1/R2) and the ring locant numbers for the compounds in panel a. The error has been corrected in the HTML and PDF versions of the article.

  • 17 March 2017

    In the version of this article initially published, some of the chemical compounds were incorrectly numbered as stereoisomers instead of racemates and some of the stereoisomers were marked with incorrect stereocenter configurations. In numerous instances throughout the main text and Online Methods, compounds 1–13 were incorrectly called 1R–13R (6 instances of 13R are correct and were left unchanged). In the legend for Figure 5: 1S, 4S, 11S, 12S, 13S were incorrectly called 1R, 4R, 11R, 12R, 13R, respectively; in the left column of p.115: 1S, 4S, 11S were incorrectly called 1R, 4R, 11R, respectively; and in the left column of p.116: 13S was incorrectly called 13R. The errors have been corrected in the HTML and PDF versions of the article.


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Research support from the National Institutes of Health (PHS 5R37DK015556 to J.A.K.; 5R33CA132022, 5R01DK077085 to K.W.N.; 1U01GM102148 to K.W.N and P.R.G., and 5R01CA130932 to J.F.), The Breast Cancer Research Foundation (to B.S.K.), BallenIsles Men's Golf Association (to J.C.N.), Frenchman's Creek Women for Cancer Research (to S.S.), Susan G. Komen for the Cure (PDF12229484 to IK), and the National Natural Science Foundation of China (81172935, 81373255, 81573279), Hubei Province's Outstanding Medical Academic Leader Program (to H.-B.Z.). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (NIGMS) (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or the NIH.

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S.S. and J.C.N. contributed equally to this work. S.S. and J.C.N. designed and performed experiments, and wrote the manuscript; N.E.B., V.C., and J.N. performed in vitro experiments; P.R.G., S.N., V.D. and D.G. designed, performed and interpreted HDX based experiments; J.F. and I.K. contributed mammosphere assays; B.S.K., N.B. and Y.Z. designed and contributed experiments including in vivo experiments in mice; H-.B.Z., J.A.K., and J.M. designed, synthesized and performed chemical analysis of compounds; B.S.K. and J.A.K. contributed in writing and revising of the manuscript; K.W.N. designed experiments and wrote the manuscript.

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Correspondence to Kendall W Nettles.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–16. (PDF 4539 kb)

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Srinivasan, S., Nwachukwu, J., Bruno, N. et al. Full antagonism of the estrogen receptor without a prototypical ligand side chain. Nat Chem Biol 13, 111–118 (2017). https://doi.org/10.1038/nchembio.2236

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