Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2,3-dioxygenase activity
Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2,3-dioxygenase activity
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DOI：
10.1016/j.bmcl.2018.07.034
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发表时间：
2018-09-15
影响因子：
2.7
通讯作者：
Matsuno, Kenji
中科院分区：
文献类型：
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作者：
Fukuda, Miwa;Sasaki, Tomomi;Matsuno, Kenji
犬尿氨酸是由吲哚胺2，3-双加氧酶（IDO）催化的色氨酸生物合成的。犬尿氨酸产生的消除被认为是免疫癌症治疗的有希望的治疗靶点。在我们的IDO抑制剂项目过程中，IDO抑制剂1的异硫杂环戊烯部分的正式环化得到5-Cl-苯并咪唑衍生物2b-6，其抑制重组人IDO（rhIDO）活性和细胞犬尿氨酸产生。2b-6的进一步衍生化提供了细胞犬尿氨酸产生的强效抑制剂2 i（IC 50 = 0.34 μ M），其对rhIDO的酶活性产生的影响出乎意料地很小。作用机制的阐明揭示了化合物2 i通过抑制IFN-γ处理的A431细胞中的STAT 1表达而在蛋白质水平上抑制IDO表达。犬尿氨酸产生抑制剂2 i有望成为免疫癌症治疗新方法的一个有希望的起点。
Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production. Further derivatisation of 2b-6 provided the potent inhibitor of cellular kynurenine production 2i (IC50 = 0.34 mu M), which unexpectedly exerted little effect on the enzymatic activity of rhIDO. Elucidation of the mechanism of action revealed that compound 2i suppresses IDO expression at the protein level by inhibiting STAT1 expression in IFN-gamma-treated A431 cells. The kynurenine-production inhibitor 2i is expected to be a promising starting point for a novel approach to immunological cancer treatment.