Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer
Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer
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发现用于治疗非小细胞肺癌的膦酰胺IDO1抑制剂
DOI：
10.1016/j.ejmech.2019.111629
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发表时间：
2019-11-15
影响因子：
6.7
通讯作者：
Bian, Jinlei
中科院分区：
文献类型：
--
作者：
Du, Qianming;Feng, Xi;Bian, Jinlei
靶向吲哚胺2，3-双加氧酶1（IDO 1）已被确定为开发癌症免疫治疗的有吸引力的方法。本研究设计、合成了一系列含磷酰胺酯的化合物，并对其抑制IDOL的活性进行了评价。其中化合物16、17和26具有较好的IDO 1抑制活性（HeLa IDO 1 IC 50 = 10-21 nM，hIDO 1 IC 50 = 78 - 121 nM），并显示出较好的理化性质。此外，基于可比较的PK特征和优异的IDO 2/TDO抑制效力，选择代表性化合物16用于进一步生物评价，并且表征为在体内抑制刘易斯细胞的肺转移（77%抑制率）中具有良好的功效。因此，化合物16可能是用于进一步评价的潜在和有效的药剂。(C)2019 Elsevier Masson SAS。All rights reserved.
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 IDOL. Among them, compounds 16,17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10-21 nM, hIDO1 IC50 = 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. (C) 2019 Elsevier Masson SAS. All rights reserved.