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Published on: July 17, 2020
Discovery of a Dual IDO1/TDO Inhibitor That Modulates Enzymatic Activity and IDO1/SHP-2 Signaling
Sarah Jane Rezzi1, Andrea Butticè1, Salvatore Villani1
1Department of Pharmaceutical Sciences, Università Degli Studi Del Piemonte Orientale, Novara 28100, Italy.
Journal of Medicinal Chemistry
|July 22, 2026
Summary
A new compound, 66, balances inhibition of IDO1 and TDO enzymes, reducing cancer cell growth. This offers a novel approach beyond solely targeting catalytic IDO1 activity.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Biology
Background:
- Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors face clinical challenges due to bypass by tryptophan 2,3-dioxygenase (TDO) and nonenzymatic signaling.
- IDO1 blockade can paradoxically promote tumor progression through stabilized signaling states.
Purpose of the Study:
- To develop a novel small molecule targeting both enzymatic and nonenzymatic functions of the IDO1/TDO axis.
- To investigate the therapeutic potential of a balanced IDO1/TDO inhibitor in cancer.
Main Methods:
- Optimization of VS-15 led to the discovery of compound 66, an ortho-benzamidourea derivative.
- Assessed compound 66 for metabolic stability, IDO1/TDO inhibition, and apo-enzyme targeting.
- Evaluated compound 66's effects on kynurenine pathway output, IDO1/SHP-2 interaction, and cancer cell proliferation/migration.
Main Results:
- Compound 66 demonstrated improved metabolic stability and balanced inhibition of both IDO1 and TDO.
- Spectroscopic data indicated targeting of the apo-enzyme form.
- 66 reduced kynurenine pathway metabolites, attenuated IDO1/SHP-2 interaction, and inhibited cancer cell proliferation and migration.
Conclusions:
- Compound 66 acts as a chemical probe for IDO1/TDO axis functions.
- Multimodal inhibition of catalytic and noncatalytic pathways offers an alternative to current IDO1 inhibition strategies.
- Supports small-molecule modulation of immune-metabolic pathways for cancer therapy.
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