Discovery of a Dual IDO1/TDO Inhibitor That Modulates Enzymatic Activity and IDO1/SHP‑2 Signaling

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors have shown limited clinical translation, partly because IDO1 blockade can be bypassed by tryptophan 2,3-dioxygenase (TDO) and may stabilize nonenzymatic IDO1 signaling states that promote tumor progression. Here, we report compound 66, an ortho-benzamidourea derivative obtained through the optimization of VS-15. Compound 66 displayed improved metabolic stability, balanced IDO1/TDO inhibition, and spectroscopic behavior consistent with apo-enzyme targeting. In tumor cells, 66 reduced kynurenine-pathway output and attenuated the IDO1/SHP-2 interaction, counteracting IDO1-driven noncatalytic signaling. This multimodal profile was associated with the inhibition of cancer cell proliferation and migration. Compound 66 therefore represents a chemical probe for dissecting enzymatic and signaling functions within the IDO1/TDO axis and supports small-molecule modulation of both catalytic and noncatalytic immune-metabolic pathways as an alternative to purely catalytic IDO1 inhibition or complete IDO1 degradation.