Indolamine-2,3-dioxygenase (IDO) is an enzyme involved in the kynurenine pathway that produces kynurenine from tryptophan. Overexpression of IDO is manipulated by specific cancer cell lines in order to become immunoresistant. Inhibition of this enzyme is of great interest in order to couple it to current immunotherapies and make them more efficacious and specific in their targets. The naphthoquinone adduct 12,13-Dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (TU100) was previously synthesized and has promise as a chemotherapeutic agent. Interestingly, it was also identified as an inhibitor of luciferase, a member of the oxygenase class of enzymes. Based on this observation we hypothesized that TU100 might inhibit other important enzymes in this class, such as IDO. To test this idea, IDO expression was induced in tissue culture cells using growth factors. A cell extract was then prepared and IDO activity measured in the presence and absence of TU100 using an absorbance-based assay which measured the presence or absence of kynurenine at 480nm. These initial results were inconclusive, however, so purified and active IDO was purchased from a commercial supplier. The ability of TU100 (and structural derivatives) to inhibit IDO enzyme activity was then examined directly.

Identification of novel indoleamine-2,3-dioxygenase inhibitors as potential immunotherapy additives

2019 Spring National Meeting

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