发现膦酰胺基 IDO1 抑制剂用于治疗非小细胞肺癌。
Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.
机构信息
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
出版信息
Eur J Med Chem. 2019 Nov 15;182:111629. doi: 10.1016/j.ejmech.2019.111629. Epub 2019 Aug 18.
Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC = 10-21 nM, hIDO1 IC = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
靶向吲哚胺 2,3-双加氧酶 1（IDO1）已被确定为癌症免疫治疗的一种有吸引力的方法。在这项研究中，设计、合成了一系列含有膦酰胺酯的化合物，并评估了它们对 IDO1 的抑制活性。其中，化合物 16、17 和 26 具有良好的 IDO1 抑制活性（HeLa IDO1 IC=10-21 nM，hIDO1 IC=78-121 nM），被选择进行进一步研究，并表现出良好的理化性质。此外，基于相当的 PK 特征和优异的 IDO2/TDO 抑制效力，代表性化合物 16 被选择进行进一步的生物评价，并表现出良好的抑制 Lewis 细胞肺转移（抑制率 77%）的疗效。因此，化合物 16 可能是一种有潜力和有效的药物，值得进一步评估。
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