ArticleJournal of medicinal chemistry2026
Discovery of a Dual IDO1/TDO Inhibitor That Modulates Enzymatic Activity and IDO1/SHP-2 Signaling.
Sarah Jane Rezzi, Andrea Butticè, Salvatore Villani, Gaia Lesca, Sofia Rossini, Eleonora Panfili, Daniele Mazzoletti, Elia Bari, Davide Violante, Marta Serafini and 9 more
Abstract read
In one paragraphArticle in Journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
19 authors.
Sarah Jane RezziDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0009-0004-9471-0536 Andrea ButticèDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Salvatore VillaniDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Gaia LescaDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Sofia RossiniDepartment of Medicine and Surgery, University of Perugia, Perugia06132, Italy.
Eleonora PanfiliDepartment of Medicine and Surgery, University of Perugia, Perugia06132, Italy.
Daniele MazzolettiDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Elia BariDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Davide ViolanteDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Marta SerafiniDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0002-5305-8359 Alberto MassarottiDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0001-9306-8845 Maria Teresa PallottaDepartment of Medicine and Surgery, University of Perugia, Perugia06132, Italy.ORCID 0000-0002-0417-1638 Silvio AprileDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0003-4804-9543 Silvia FallariniDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.
Erika Del GrossoDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0002-2398-5944 Rita Maria Concetta Di MartinoDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0003-2287-3331 Riccardo MiggianoDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0002-2159-3314 Tracey PiraliDepartment of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara28100, Italy.ORCID 0000-0003-3936-4787 Funding
Associazione Italiana per la Ricerca sul Cancro 22568Associazione Italiana per la Ricerca sul Cancro 29452European Commission DO120P8HZTMinistero dell?Istruzione, dell?Universit? e della Ricerca ECS00000036
6 · The paper itselfAbstract
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.
Indexed as
Drug DiscoveryEnzyme InhibitorsIndoleamine-Pyrrole 2,3,-DioxygenaseSignal TransductionTryptophan OxygenaseAnimalsCell Line, TumorCell MovementCell ProliferationHumansStructure-Activity RelationshipEnzyme InhibitorsIDO1 protein, humanIndoleamine-Pyrrole 2,3,-DioxygenaseTryptophan Oxygenase
Identifiers
PMID42483959
PMCPMC13492295
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