Indoleamine-2,3-dioxygenase-1 (IDO-1), as well as the related Indoleamine-2,3-dioxygenase-2 ( IDO2) and tryptophan 2,3-dioxygenase (TDO), are intracellular heme-containing enzymes which catalyze the first, and rate-determining, step in the metabolism of tryptophan to <i>N-</i>formylkynurenine. The depletion of tryptophan and accumulation of kynurenine pathway metabolites can lead to immunosuppression via T-reg activation and T-eff suppression and apoptosis. Both IDO1 and TDO2 are up-regulated by many cancer cells, and increased IDO1 and/or TDO activity in tumors can give rise to suppressed host immune response to the tumor. The expression of IDO1 is highly correlated with PD-1 expression in tumors, and the clinical efficacy of an IDO1 inhibitor in combination with a PD-1 inhibitor has been demonstrated by the combination of Epacadostat (an IDO1-selective inhibitor, Incyte) and Pembrolizumab (anti-PD-1 antibody, Merck). In this presentation, we will describe the discovery and optimization of a novel class of hydroxyamidine-based heme-binding IDO1 inhibitors featuring a very unique A-pocket piece. The lead molecule from this chemical series demonstrates very good potency, isoform selectivity, and off-target profile as well as favorable pharmacokinetics. Additional studies to evaluate the chemical stability and to confirm the drug-like properties of the novel A-pocket piece will also be discussed.

Discovery and optimization of potent, selective, and orally available IDO1 heme-binding inhibitors featuring a novel A-pocket piece

256th National Meeting (2018)

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