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  3. Discovery of imidazole-based apo-IDO1 inhibitors: rational design, synthesis, and biological evaluation

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.
Jin-Hong Wu 1,  Yue-Hui Xing 2,  Xing-Hua Wang 2,  Wen-Jing Gao 2,  Xiang-Yu Liu 2,  Jian-Min Yue 3,  Jin-Hai Yu 4
Affiliations

Affiliations

  • 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].
PMID: 41692313 DOI: 10.1016/j.bmcl.2026.130586
Abstract

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.

Keywords

Apo-IDO1 inhibitors; Heme displacement; Imidazole; Pan-tissue inhibition; Structure-activity relationship (SAR).

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