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Research ArticleArticle

In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

Ashley J. Parks, Michael P. Pollastri, Mark E. Hahn, Elizabeth A. Stanford, Olga Novikov, Diana G. Franks, Sarah E. Haigh, Supraja Narasimhan, Trent D. Ashton, Timothy G. Hopper, Dmytro Kozakov, Dimitri Beglov, Sandor Vajda, Jennifer J. Schlezinger and David H. Sherr
Molecular Pharmacology November 2014, 86 (5) 593-608; DOI: https://doi.org/10.1124/mol.114.093369
Ashley J. Parks
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Michael P. Pollastri
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Mark E. Hahn
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Elizabeth A. Stanford
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Olga Novikov
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Diana G. Franks
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Sarah E. Haigh
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Supraja Narasimhan
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Trent D. Ashton
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Timothy G. Hopper
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Dmytro Kozakov
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Dimitri Beglov
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Sandor Vajda
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Jennifer J. Schlezinger
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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David H. Sherr
Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)
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Abstract

The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape–based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand–induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)– and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10−7 M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy.

Footnotes

    • Received April 28, 2014.
    • Accepted August 22, 2014.
  • J.J.S and D.H.S. contributed equally to this manuscript.

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [R01-ES11624, P42-ES007381, R01-ES006272] and National Institute of General Medical Sciences [R01-GM064700]; the Art beCAUSE Breast Cancer Foundation; The Mary Kay Foundation; and a Boston University Ignition Award.

  • dx.doi.org/10.1124/mol.114.093369.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

Identification of an AHR Antagonist

Ashley J. Parks, Michael P. Pollastri, Mark E. Hahn, Elizabeth A. Stanford, Olga Novikov, Diana G. Franks, Sarah E. Haigh, Supraja Narasimhan, Trent D. Ashton, Timothy G. Hopper, Dmytro Kozakov, Dimitri Beglov, Sandor Vajda, Jennifer J. Schlezinger and David H. Sherr
Molecular Pharmacology November 1, 2014, 86 (5) 593-608; DOI: https://doi.org/10.1124/mol.114.093369

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Research ArticleArticle

Identification of an AHR Antagonist

Ashley J. Parks, Michael P. Pollastri, Mark E. Hahn, Elizabeth A. Stanford, Olga Novikov, Diana G. Franks, Sarah E. Haigh, Supraja Narasimhan, Trent D. Ashton, Timothy G. Hopper, Dmytro Kozakov, Dimitri Beglov, Sandor Vajda, Jennifer J. Schlezinger and David H. Sherr
Molecular Pharmacology November 1, 2014, 86 (5) 593-608; DOI: https://doi.org/10.1124/mol.114.093369
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