Department of Geriatrics, Beijing Hospital, National Center of Gerontology, Dongcheng, Beijing 100730, P.R. China.
Research Division of Clinical Pharmacology, Τhe First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Int J Mol Med. 2018 May;41(5):2450-2460. doi: 10.3892/ijmm.2018.3505. Epub 2018 Feb 20.
Sphingosine kinases (SphKs) catalyze the conversion of the sphingosine to the promitogenic/migratory product, sphingosine-1-phosphate (S1P). SphK/S1P pathway has been linked to the progression of cancer and various other diseases including allergic inflammatory disease, cardiovascular diseases, rejection after transplantation, the central nervous system, and virus infections. Therefore, SphKs represent potential new targets for developing novel therapeutics for these diseases. The history and development of SphK inhibitors are discussed, summarizing SphK inhibitors by their structures, and describing some applications of SphK inhibitors. We concluded: i) initial SphK inhibitors based on sphingosine have low specificity with several important off-targets. Identification the off-targets that would work synergistically with SphKs, and developing compounds that target the unique C4 domain of SphKs should be the focus of future studies. ii) The modifications of SphK inhibitors, which are devoted to increasing the selectivity to one of the two isoforms, now focus on the alkyl length, the spacer between the head and linker rings, and the insertion and the position of lipidic group in tail region. iii) SphK/S1P signaling pathway holds therapeutic values for many diseases. To find the exact function of each isoform of SphKs increasing the number of SphK inhibitor clinical trials is necessary.
鞘氨醇激酶（SphKs）催化鞘氨醇向促有丝分裂/迁移产物——鞘氨醇-1-磷酸（S1P）的转化。SphK/S1P 途径与癌症和各种其他疾病的进展有关，包括过敏性炎症性疾病、心血管疾病、移植后的排斥反应、中枢神经系统和病毒感染。因此，SphKs 代表了为这些疾病开发新型治疗方法的潜在新靶点。本文讨论了 SphK 抑制剂的历史和发展，根据其结构对 SphK 抑制剂进行了总结，并描述了 SphK 抑制剂的一些应用。我们得出结论：i）最初基于鞘氨醇的 SphK 抑制剂特异性低，有几个重要的非靶点。确定与 SphKs 协同作用的非靶点，并开发靶向 SphKs 独特 C4 结构域的化合物，应该是未来研究的重点。ii）为了提高对两种同工型之一的选择性而对 SphK 抑制剂进行的修饰，现在侧重于烷基长度、头部和连接环之间的间隔、尾部区域中脂基团的插入和位置。iii）SphK/S1P 信号通路对许多疾病具有治疗价值。为了找到每个 SphK 同工型的确切功能，有必要增加 SphK 抑制剂临床试验的数量。
