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IDO1/TDO* mediate substantial immunosuppressive effects through the metabolism of tryptophan (Trp) to kynurenine (Kyn). The consequent decrease in Trp suppresses T cell activity by multiple mechanisms, including the activation of GCN2 and mTOR pathways. Additionally, increased levels of Kyn further enhance the effect of Trp metabolism by engagement of aryl hydrocarbon receptor and potentially enhancing the number and activity of regulatory T cells. Taken together, expression of IDO1 and TDO in the tumor micro-environment dampens tumor-specific effector T cell response, and elevated expression of IDO1/TDO correlates with reduced survival of cancer patients. IDO1 selective inhibitors have already demonstrated clinical anti-tumor activity for certain tumor types. Therefore, targeting the Trp/Kyn pathway via simultaneous inhibition of IDO1 and TDO enzymes has the potential to bring enhanced benefit to cancer patients by relieving immunosuppression in a wide variety of tumor types. We have discovered a novel, highly potent, small molecule IDO1/TDO dual inhibitor, RG70099, with favorable preclinical oral bioavailability and safety profile. RG70099 potently inhibits both enzymes in cell based assays (IDO1 IC50: Our data show for the first time that a dual inhibition of IDO1 and TDO significantly reduces Kyn levels in preclinical tumor models. RG70099 is a potent, dual-selective IDO1 and TDO small molecule inhibitor with favorable pharmaceutical and pharmacokinetic properties that has the potential to relieve immunosuppression by both IDO1 and TDO and activate anti-tumor immune responses for a broad range of cancer types. *IDO1: Indoleamine 2,3-Dioxygenase 1; TDO: Tryptophan 2,3-Dioxygenase Citation Format: Gabor Gyulveszi, Christine Fischer, Massimiliano Mirolo, Martin Stern, Luke Green, Maurizio Ceppi, Haiyan Wang, Beatrice Bürgi, Andreas Staempfli, Wolfgang Muster, Robert van Waterschoot, Andreas Gloge, Hadassah Sade, Irina Klaman, Gabriele Hoelzlvimmer, Arjun Surya, Monali Banerjee, Ritesh Shrivastava, Sandip Middya, Dharmendra Yadav, Sourav Basu, Gonzalo Acuna. RG70099: A novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-085.