In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo
| Autor: | Olga Novikov, Diana G. Franks, Dimitri Beglov, Sarah E. Haigh, Trent D. Ashton, Mark E. Hahn, Ashley J. Parks, Sandor Vajda, Michael P. Pollastri, Dmytro Kozakov, Elizabeth A. Stanford, David H. Sherr, Jennifer J. Schlezinger, Timothy G. Hopper, Supraja Narasimhan |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Bone Marrow Cells Triple Negative Breast Neoplasms Pharmacology Ligands Cell Line Biological Factors Mice Cell Movement In vivo Cell Line Tumor Chlorocebus aethiops medicine Animals Humans Receptor Cell Proliferation biology Cell growth Biological activity Articles Aryl hydrocarbon receptor In vitro Mice Inbred C57BL Receptors Aryl Hydrocarbon Mechanism of action COS Cells Cancer cell biology.protein Molecular Medicine Stromal Cells medicine.symptom |
| Zdroj: | Molecular Pharmacology. 86:593-608 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.114.093369 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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