Identification and optimisation of next generation inhibitors of IDO1 and TDO

Introduction The enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO1) catalyse oxidation of the essential amino acid tryptophan (Trp) leading to the formation of immunosuppressive kynurenine (Kyn) pathway metabolites that dampen the immune response in the tumour microenvironment. Both IDO1 and TDO have been shown to be up-regulated in a variety of cancers and blockade of their activity has been shown to stimulate the anti-tumour immune response in pre-clinical animal models. We have discovered multiple novel chemical series of both highly selective and dual-acting inhibitors of IDO1 and TDO. Herein we describe their in vitro and in vivo characterisation.