The dioxygenase indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the commitment step of the kynurenine (KYN) metabolic pathway. KYN is a key signaling molecule and activates the intracellular arylhydrocarbon receptor to induce immune tolerance. Recently, emerging data has revealed IDO1 as a crucial enzyme in promoting tumor immune evasion, and supports the development of selective IDO1 inhibitor as novel cancer immunotherapies. We designed and implemented a docking protocol to select virtual IDO1 inhibitors. A 3D conformer library (1.5 million entries) was generated using Open Babel from commercial compound database and docked by Autodock Vina to the crystal structure of IDO1. The 133 top-scoring virtual hits were selected and tested for their inhibitory activity of IDO1 in an in vitro biochemical assay. We successfully discovered 4 confirmed hits (IC50: &lt;50 μM) that are structurally unique and different from reported IDO1 inhibitors. The hit rate for this in silico screen is 3%. Among the 4 newly identified IDO1 inhibitors, N-(naphthalen-1-yl)-4-phenyltetrahydro-2H-pyran-4-carboxamide (IC50: 9.8 μM) is also selective against tryptophan 2,3-dioxygenase 2 (TDO2, IC50: ~100 μM). We have conducted structure-activity relationship (SAR) study and identified key structural requirements for the IDO1 inhibitory of this novel chemical class, which is supported by docking analyses. In this presentation, we will provide updated results of our SAR study as well as cellular activities of the most advanced lead molecules.

Discovery of tetrahydropyran derivatives as inhibitors of indoleamine 2,3-dioxygenase – in silico screen and structure-activity relationship studies

255th National Meeting (2018)

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