Dept. of Chemistry, Indian Institute of Technology, Kanpur, UP, India 208016
The essential amino acid tryptophan is metabolized by a family of dioxygenases and downstream enzymes that convert tryptophan to kynurenine and related metabolites. These tryptophan metabolites generate immunosuppressive effects by activating effectors in a variety of immune and tumor cells. This mechanism of immune suppression works during pregnancy to help prevent rejection of the fetus by the maternal immune system. A wide range of tumors generate kynurenine and its metabolites to suppress immune clearance mechanisms. We have generated potent enzyme inhibitors that reduce kynurenine levels in vitro, in cellular assays and in a rodent model of LPS induced inflammation. These inhibitors display good oral bioavailability and ADME properties and are suitable for tumor immunotherapy and for treatment of immune suppression associated with a variety of pathological conditions such as HIV.