Mao Long-Fei, Wang Yu-Wei, Zhao Jie, Xu Gui-Qing, Yao Xiao-Jun, Li Yue-Ming
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
School of Chemistry and Chemical Engineering, Henan Engineering Research Center of Chiral Hydroxyl Pharmaceutical, Henan Normal University, Xinxiang, China.
Front Pharmacol. 2020 Sep 30;11:579024. doi: 10.3389/fphar.2020.579024. eCollection 2020.
Tumor immunotherapy is considered to be a highlight in cancer treatment in recent years. Indoleamine 2,3-dioxygenase 1 (IDO1) is closely related to the over expression of many cancers, and is therefore a promising target for tumor immunotherapy. To search for novel IDO1-targeting therapeutic agents, 22 icotinib-linked 1,2,3-triazole derivatives were prepared and evaluated for their inhibitory activity against IDO1. The structures of the prepared compounds were confirmed withH NMR, C NMR and HR MS. IDO1 inhibitory activity assay results indicated that 10 of those compounds showed remarkable inhibitory activity against IDO1, among which compound was the most potent with ICvalue of 0.37 μM. The binding model between the prepared compounds and IDO1 was studied with molecular modeling study. The current study suggested that icotinib-1,2,3-triazole derivatives could be used as potential inhibitors that preferentially bind to the ferrous form of IDO1 through the formation of coordinate bond with the haem iron.
肿瘤免疫疗法被认为是近年来癌症治疗领域的一个亮点。吲哚胺2,3-双加氧酶1（IDO1）与多种癌症的过度表达密切相关，因此是肿瘤免疫疗法的一个有前景的靶点。为了寻找新型IDO1靶向治疗药物，制备了22种与埃克替尼相连的1,2,3-三唑衍生物，并评估了它们对IDO1的抑制活性。通过1H NMR、13C NMR和HR MS对所制备化合物的结构进行了确证。IDO1抑制活性测定结果表明，其中10种化合物对IDO1表现出显著的抑制活性，其中化合物 活性最强，IC50值为0.37 μM。通过分子模拟研究了所制备化合物与IDO1之间的结合模式。当前研究表明，埃克替尼-1,2,3-三唑衍生物可作为潜在抑制剂，通过与血红素铁形成配位键优先结合IDO1的亚铁形式。
