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

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.