State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Eur J Med Chem. 2018 Sep 5;157:423-436. doi: 10.1016/j.ejmech.2018.08.013. Epub 2018 Aug 7.
Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among them, compounds T16, T44, T47, T49, T53 and T54 displayed potent IDO1 inhibitory activities with IC values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28, T44 and T53 decreased the kynurenine levels in rat plasma by 30%-50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC = 120 nM) showed promising TDO inhibition (IC 72 nM) and was identified as an IDO1/TDO dual inhibitor.
色氨酸降解的吲哚胺 2,3-双加氧酶 1（IDO1）介导的犬尿氨酸途径被确定为癌症免疫治疗中一种有吸引力的新型靶点。在这项研究中，合成了一系列新型萘醌衍生物，并对其抑制 IDO1 的活性进行了表征和评估，并研究了它们的构效关系。其中，化合物 T16、T44、T47、T49、T53 和 T54 对 IDO1 具有很强的抑制活性，IC 值在 18-61nM 之间，比正在进行 III 期临床试验评估的 INCB024360 更有效。此外，化合物 T28、T44 和 T53 使大鼠血浆中的犬尿氨酸水平降低了 30%-50%。对具有优异 IDO1 抑制活性的化合物也进行了对色氨酸 2,3-双加氧酶（TDO）的抑制活性评估。其中，化合物 T28（IDO1 IC = 120nM）对 TDO 具有良好的抑制活性（IC 72nM），被鉴定为 IDO1/TDO 双重抑制剂。
