This project aims to identify possible environmental endocrine disrupters working by an unusual mechanism that operates after the interaction of ligands with nuclear hormone receptors, namely, by the direct inhibition or potentiation of the nuclear hormone receptor/coactivator interaction itself. This goal will be accomplished by developing time-resolved fluorescence assays that probe in a robust and reliable manner the interaction of the nuclear receptors with coactivators. These assays are adaptable to high-throughput screening, and will be used at the Emory University Molecular Libraries Screening Center, an NIH-funded Roadmap Research Resource to which we have obtained access, to identify possible coactivator binding inhibitors (CBIs) or coactivator binding potentiators (CBPs) that might be present in the environment. After compounds have been identified as possible disrupters or potentiators of endocrine function, they will be subject to secondary assays to confirm that they indeed act through these unusual CBI or CBP mechanisms. These assays will also use fluorescence resonance energy transfer methodology, but with carefully selected alterations in the concentrations of integral components to elucidate mechanism. Finally, cell-based assays such as mammalian-2-hybrid, cotransfection reporter gene assays, or monitoring of hormone-responsive gene products will more definitively demonstrate the possible biological or physiological effects arising from exposure to these compounds. This project should help pinpoint a novel endocrine disruption site within the nuclear receptor signaling pathway and identify the compounds that work at this level. It should also help identify possible CBIs or CBPs present in the environment or in commonly used products that could be causing alterations in the pattern of genome transcription by an unusual mechanism, due to the interruption or the potentiation of nuclear receptor-regulated signal transduction that operates at a post ligand-receptor interaction level. Ultimately, this project should help in identifying harmful compounds present within our environment and, hopefully, guide measures to minimize exposure of the public to these substances. Endocrine disrupters are exogenous compounds that interfere with the endocrine system, altering hormone action and the messages it sends throughout the body. This project aims to identify possible endocrine disrupters that act by an unusual mechanism. Large numbers of compounds will be screened to determine structural featurs of those that inhibit or potentiate endocrine action by this unusual process. With this information, steps could be taken to minimize human exposure to these novel types of endocrine disrupters.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Humble, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
Zip Code
Bertini, Simone; De Cupertinis, Andrea; Granchi, Carlotta et al. (2011) Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes. Eur J Med Chem 46:2453-62
Jeyakumar, M; Carlson, Kathryn E; Gunther, Jillian R et al. (2011) Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. J Biol Chem 286:12971-82
Moore, Terry W; Gunther, Jillian R; Katzenellenbogen, John A (2010) Probing the topological tolerance of multimeric protein interactions: evaluation of an estrogen/synthetic ligand for FK506 binding protein conjugate. Bioconjug Chem 21:1880-9
Kim, Sung Hoon; Gunther, Jillian R; Katzenellenbogen, John A (2010) Monitoring a coordinated exchange process in a four-component biological interaction system: development of a time-resolved terbium-based one-donor/three-acceptor multicolor FRET system. J Am Chem Soc 132:4685-92
Gunther, Jillian R; Du, Yuhong; Rhoden, Eric et al. (2009) A set of time-resolved fluorescence resonance energy transfer assays for the discovery of inhibitors of estrogen receptor-coactivator binding. J Biomol Screen 14:181-93
Gunther, Jillian R; Parent, Alexander A; Katzenellenbogen, John A (2009) Alternative inhibition of androgen receptor signaling: peptidomimetic pyrimidines as direct androgen receptor/coactivator disruptors. ACS Chem Biol 4:435-40
Williams, Anna B; Weiser, Patrick T; Hanson, Robert N et al. (2009) Synthesis of biphenyl proteomimetics as estrogen receptor-alpha coactivator binding inhibitors. Org Lett 11:5370-3
Parent, Alexander A; Gunther, Jillian R; Katzenellenbogen, John A (2008) Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding. J Med Chem 51:6512-30
Kim, Sung Hoon; Gunther, Jillian R; Katzenellenbogen, John A (2008) Nonclassical SNAPFL analogue as a Cy5 resonance energy transfer partner. Org Lett 10:4931-4
Gunther, Jillian R; Moore, Terry W; Collins, Margaret L et al. (2008) Amphipathic benzenes are designed inhibitors of the estrogen receptor alpha/steroid receptor coactivator interaction. ACS Chem Biol 3:282-6

Showing the most recent 10 out of 11 publications