Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Molecules. 2020 Mar 23;25(6):1447. doi: 10.3390/molecules25061447.
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives as showed potent IDO1 inhibition, with IC values of 0.1-0.6 μM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound within IDO1. Compound was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of -treated mice showed no obvious reduction compared with the control group. Overall, compound is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.
吲哚胺 2,3-双加氧酶 1（IDO1）是一种含血红素的细胞内酶，催化色氨酸代谢的第一步和限速步骤，是癌症治疗的重要免疫治疗靶点。在这项研究中，我们设计并合成了一系列新的化合物作为潜在的 IDO1 抑制剂。然后评估这些化合物对 IDO1 和色氨酸 2,3-双加氧酶（TDO）的抑制活性。其中，三个苯脲衍生物 表现出强烈的 IDO1 抑制作用，IC 值为 0.1-0.6 μM，没有化合物表现出 TDO 抑制活性。通过分子对接，我们预测了化合物 在 IDO1 中的结合模式。进一步通过测定其体内药代动力学特征和抗肿瘤功效来研究化合物 。药代动力学研究表明，化合物 在小鼠体内具有良好的性质，其血浆清除率（22.45 mL/min/kg）适中，半衰期（11.2 h）可接受，口服生物利用度（87.4%）高。化合物 每天以 15 mg/kg 口服给药在 B16F10 皮下异种移植模型中显示出 40.5%的肿瘤生长抑制（TGI），每天以 30 mg/kg 口服给药在 PAN02 皮下异种移植模型中显示出 34.3%的 TGI。此外，-处理组小鼠的体重与对照组相比没有明显下降。总的来说，化合物 是开发 IDO1 抑制剂和抗肿瘤药物的有力先导化合物。
