Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy

Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.