Discovery of a Dual IDO1/TDO Inhibitor That Modulates Enzymatic Activity and IDO1/SHP-2 Signaling
High Resolution Image Download MS PowerPoint Slide 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.
Authors
- Tracey Pirali (ORCID: https://orcid.org/0000-0003-3936-4787)
- Sofia Rossini (ORCID: https://orcid.org/0000-0001-6429-9425)
- Silvio Aprile (ORCID: https://orcid.org/0000-0003-4804-9543)
- Elia Bari (ORCID: https://orcid.org/0000-0003-0241-0620)
- Ciriana Orabona (ORCID: https://orcid.org/0000-0003-3113-0572)
- Daniele Mazzoletti (ORCID: https://orcid.org/0000-0002-0711-8269)
- Maria Teresa Pallotta (ORCID: https://orcid.org/0000-0002-0417-1638)
- Alberto Massarotti (ORCID: https://orcid.org/0000-0001-9306-8845)
- Erika Del Grosso (ORCID: https://orcid.org/0000-0002-2398-5944)
- Rita Maria Concetta Di Martino (ORCID: https://orcid.org/0000-0003-2287-3331)
- Silvia Fallarini (ORCID: https://orcid.org/0000-0001-8871-7417)
- Eleonora Panfili (ORCID: https://orcid.org/0000-0003-2466-2933)
- M. Teresa Serafini (ORCID: https://orcid.org/0000-0002-5305-8359)
- Salvatore Villani (ORCID: https://orcid.org/0000-0002-7268-4937)
- Riccardo Miggiano (ORCID: https://orcid.org/0000-0002-2159-3314)
- Sarah Jane Rezzi (ORCID: https://orcid.org/0009-0004-9471-0536)
- Andrea Butticè
- Davide Violante
- Gaia Lesca
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Perugia (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-07-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00759
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00