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Author Notes:

Correspondence: Aiming Sun, Department of Chemistry, Emory University 1515 Dickey Drive, Atlanta, GA 30322, Phone: 404-712-8680, Fax: 404-727-6689, Email: asun2@emory.edu; or John A. Katzenellenbogen, Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana IL 61801, Telephone No.: 217-333-6310, Fax No.: 217-333-7325, Email: jkatzene@uiuc.edu

Acknowledgments: We are grateful to Dr. Thota Ganesh (Emory University) for resynthesis of hit 3.


Research Funding:

We are grateful for support from the following grants: National Institutes of Health R37 DK015556 and X01 MH078953 (to J.A.K.) and U54 HG003018 (to J.P.S. and H.F.).


  • coactivator binding inhibitor
  • estrogen antagonist
  • estrogen receptor
  • molecular modeling
  • structure-activity relationships

Discovering Small Molecule Estrogen Receptor ?/Coactivator Binding Inhibitors: High-Throughput Screening, Ligand Development, and Models for Enhanced Potency


Journal Title:



Volume 6, Number 4


, Pages 654-666

Type of Work:

Article | Post-print: After Peer Review


Small molecules, namely, coactivator binding inhibitors (CBIs), that block estrogen signaling by directly inhibiting the interaction of the estrogen receptor (ER) with coactivator proteins act in a fundamentally different way than traditional antagonists, which displace the endogenous ligand estradiol. To complement our prior efforts at CBI discovery by de novo design, we used high-throughput screening to identify CBIs of novel structure and subsequently investigated two hits by analog synthesis, finding many compounds with low micromolar potencies in cell-based reporter gene assays. We examined structure-activity trends in both series, using induced-fit computational docking to propose binding poses for these molecules in the coactivator binding groove. Analysis of the structure of the ER-steroid receptor coactivator (SRC) complex suggests that all four hydrophobic residues within the SRC nuclear receptor box sequence are important binding elements. Thus, insufficient water displacement as the smaller CBIs bind at the expansive complexation site may be limiting the potency of compounds in these series, which suggests that higher potency CBIs might be found by screening compound libraries enriched in larger molecules.

Copyright information:

© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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