Discovery of imidazole-based apo-IDO1 inhibitors: rational design, synthesis, and biological evaluation
- Bioorg Med Chem Lett. 2026 Feb 13:136:130586. doi: 10.1016/j.bmcl.2026.130586.
- 1. School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
- 2. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
- 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: [email protected].
- 4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: [email protected].
This study reports the rational design, synthesis, and biological evaluation of imidazole-based apo-IDO1 inhibitors. Based on the established three-component pharmacophore model, we innovatively introduced an imidazole ring as the central linker to bridge Fragments A and B. Systematic structure-activity relationship (SAR) studies afforded the most potent compound YC-16, with an IC50 value of 0.18 ± 0.01 μM and no significant cytotoxicity. YC-16 exhibits comparable potency across diverse tissue-derived cell lines, demonstrating broad tissue selectivity. Mechanistic studies confirmed that YC-16 does not alter IDO1 expression but acts as an apo-IDO1 inhibitor through two complementary mechanisms: slow competitive displacement of heme from mature holo-IDO1 and rapid binding to the heme-binding site of immature apo-IDO1. These findings establish YC-16 as a promising pan-tissue apo-IDO1 inhibitor and provide a clear foundation for further structural optimization.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer