title: In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo.
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.
authors.affiliation: 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.).
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Parks
authors.affiliation: 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.).
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
authors.affiliation: 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.).
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hahn
authors.affiliation: 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.).
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stanford
authors.affiliation: 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.).
authors.forename: Olga
authors.initials: O
authors.lastname: Novikov
authors.affiliation: 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.).
authors.forename: Diana G
authors.initials: DG
authors.lastname: Franks
authors.affiliation: 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.).
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Haigh
authors.affiliation: 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.).
authors.forename: Supraja
authors.initials: S
authors.lastname: Narasimhan
authors.affiliation: 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.).
authors.forename: Trent D
authors.initials: TD
authors.lastname: Ashton
authors.affiliation: 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.).
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Hopper
authors.affiliation: 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.).
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kozakov
authors.affiliation: 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.).
authors.forename: Dimitri
authors.initials: D
authors.lastname: Beglov
authors.affiliation: 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.).
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
authors.affiliation: 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.).
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schlezinger
authors.affiliation: 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.) dsherr@bu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy
chemical_list: D001685:Biological Factors; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon