Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Med Chem Lett. 2021 Nov 15;52:128373. doi: 10.1016/j.bmcl.2021.128373. Epub 2021 Sep 21.
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 IC 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 在肿瘤免疫抵抗中发挥重要作用。用具有新作用机制的小分子抑制 IDO1 是 IDO1 抑制剂开发的一种潜在策略。基于我们最初与全酶 IDO1 结合的尿素衍生化合物，通过骨架跃迁，设计了一系列二异丁基氨基苯羟胺化合物。出乎意料的是，这种新型 IDO1 抑制剂不是针对 IDO1 蛋白的全酶形式，而是取代血红素并与它的脱辅基形式结合。代表性化合物 I-4 在基于细胞的 IDO1 测定中具有中等效力，IC 值为 0.44 μM，有可能被开发用于 IDO1 相关的癌症治疗。
