TY - JOUR T1 - In Silico Identification of an Aryl Hydrocarbon Receptor (AHR) Antagonist with Biological Activity In Vitro and In Vivo JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.093369 SP - mol.114.093369 AU - Ashley J Parks AU - Michael P Pollastri AU - Mark E Hahn AU - Elizabeth A Stanford AU - Olga Novikov AU - Diana G Franks AU - Sarah E Haigh AU - Supraja Narasimhan AU - Trentt D Ashton AU - Timothy G Hopper AU - Dima Kozakov AU - Dmitri Beglov AU - Sandor Vajda AU - Jennifer J Schlezinger AU - David H Sherr Y1 - 2014/08/26 UR - http://molpharm.aspetjournals.org/content/early/2014/08/26/mol.114.093369.abstract N2 - The aryl hydrocarbon receptor (AHR) is critically involved in several physiological processes, including cancer progression and multiple immune phenomena. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were utilized to identify novel AHR ligands based on previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, CB7993113, was further tested for its ability to block three AHR-dependent biological 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 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 x 10-7 M) effectively reduced invasion of human breast cancer cells in 3D cultures and blocked tumor cell migration in 2D 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. ER -