More recently, a role for the AHR in immunology has been emphasized by reports that activation of this receptor with ligands, such as TCDD, can lead to the generation of regulatory T-cells, while activation with other ligands, such as formylindolo carbazole can lead to Th17 cell formation. The potential clinical importance of this finding is supported by the observation that TCDD is able to ameliorate the symptoms of experimental autoimmune encephalomyelitis in mice, whereas FICZ aggravates this syndrome. Additional studies have supported the idea that ligands can play a role in improving allograft acceptance after transplantation. The importance of the AHR in immunology has also been extended by a series of papers demonstrating the central importance of this receptor in the presence and maintenance of intraepithelial lymphocytes and lymphoid tissue inducer cells in the gut, highlighting that the AHR and its ligands play a role in normal physiology of the immune system and response to the outside environment. We have begun a search for agonists and antagonists of the AHR as part of an effort to develop a new class of receptor ligands with therapeutic potential for the treatment of vascular or immunological disease. Our initial strategy is to screen compounds that are pharmacologically well studied and that pose less environmental or health risks as compared to TCDD. Our approach to initially screen a library of compounds with known biological activity was chosen for three reasons. First, well studied compounds hold greater probability of prior toxicological and pharmacological characterization and thus may move into clinical settings more quickly. Second, identification of AHR ligands in classes of pharmacologically active compounds already in the clinic could shed additional insights into their mode of action, as well as identify compounds with understandable offtarget effects. Third, pharmacological information about novel AHR agonists could provide insight into the endogenous mechanism of 7-Deazaadenosine action of this receptor or reveal the biological ML240 pathways in which the receptor participates during development. As one result of this effort, we have discovered that, a known VEGFR-2 kinase inhibitor that progressed to Phase III clinical trial
