Indoleamine-2,3-dioxygenase 1 (IDO-1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in the conversion of tryptophan to kynurenine.  The action of IDO-1 leads to increased levels of kynurenine and reduced levels of tryptophan in the serum and tumor microenvironment of cancer patients, which results in suppression of local immune response and subsequent growth of the tumor.  Over-expression of IDO-1 has been reported in many tumor types and has been correlated with poor prognosis.  IDO-1 is an attractive immuno-oncology target that is amenable to perturbation by small molecules and has been the focus of efforts by many academic and pharmaceutical company research teams.  We set out to identify highly potent small molecule inhibitors of IDO-1 with good selectivity over tryptophan-2,3-dioxygenase (TDO).  We investigated numerous chemotypes with differentiated mechanisms of action in their inhibition of IDO-1.  Many of these leads were found to interact with IDO-1 in a manner that promotes heme displacement from the enzyme, leading to an inactive holoenzyme-inhibitor complex.  This presentation will summarize the preclinical evaluation of a selective IDO-1 inhibitor that induces the loss of heme and has been advanced into Phase I clinical trials for the treatment of cancer.

Discovery of a selective inhibitor of indoleamine-2,3-dioxygenase for use in the therapy of cancer

253rd National Meeting (2017)

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