Deakin University

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In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo

journal contribution
posted on 2014-11-01, 00:00 authored by A J Parks, M P Pollastri, M E Hahn, E A Stanford, O Novikov, D G Franks, S E Haigh, S Narasimhan, Trent Ashton, T G Hopper, D Kozakov, D Beglov, S Vajda, J J Schlezinger, D H Sherr
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.



Molecular pharmacology






593 - 608


American Society for Pharmacology and Experimental Therapeutics


Bethesda, Md.







Publication classification

C Journal article; C1.1 Refereed article in a scholarly journal

Copyright notice

2014, The American Society for Pharmacology and Experimental Therapeutics