Immunomodulating enzyme IDO1 plays an important role in tumor immune resistance. Inhibiting IDO1 by small molecules with new mechanism of action is a potential strategy in IDO1 inhibitor development. Based on our urea derived compound originally binding with holo-IDO1, through scaffold hopping, a series of diisobutylaminophenyl hydroxyamidine compounds were designed. Unexpectedly, this novel class of IDO1 inhibitor does not target the holo form of IDO1 protein but displaces heme and binds to its apo form. Representative compound I-4 exhibits moderate potency with IC₅₀ value of 0.44 μM in cell-based IDO1 assay, which has the potential to be developed for IDO1-related cancer treatment.

免疫调节酶IDO1在肿瘤免疫抵抗中起重要作用。通过具有新作用机制的小分子抑制IDO1是IDO1抑制剂开发的潜在策略。基于我们最初与holo-IDO1结合的尿素衍生化合物，通过支架跳跃，设计了一系列二异丁基氨基苯基羟基脒化合物。出乎意料的是，这种新型 IDO1 抑制剂并不针对 IDO1 蛋白的全息形式，而是取代血红素并与其载脂蛋白形式结合。代表性化合物I-4在基于细胞的 IDO1 测定中表现出中等效力，IC ₅₀值为 0.44 μM，具有开发用于 IDO1 相关癌症治疗的潜力。