Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.
Curr Pharm Des. 2019;25(9):956-968. doi: 10.2174/1381612825666190404115424.
Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to form the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P is an important lipid mediator with a wide range of biological functions; it is also involved in a variety of diseases such as inflammatory diseases, Alzheimer's disease and cancer.
This review reports the recent advancement in the research of SphKs inhibitors. Our purpose is also to provide a complete overview useful for underlining the features needed to select a specific pharmacological profile.
Two distinct mammalian SphK isoforms have been identified, SphK1 and SphK2. These isoforms are encoded by different genes and exhibit distinct subcellular localizations, biochemical properties and functions. SphK1 and SphK2 inhibition can be useful in different pathological conditions.
SphK1 and SphK2 have many common features but different and even opposite biological functions. For this reason, several research groups are interested in understanding the therapeutic usefulness of a selective or non-selective inhibitor of SphKs. Moreover, a compensatory mechanism for the two isoforms has been demonstrated, thus leading to the development of dual inhibitors.
神经鞘氨醇激酶（SphKs）催化神经鞘氨醇磷酸化为具有生物活性的鞘脂代谢物 1-磷酸鞘氨醇（S1P）。S1P 是一种重要的脂质介质，具有广泛的生物学功能；它还涉及多种疾病，如炎症性疾病、阿尔茨海默病和癌症。
本综述报告了 SphK 抑制剂研究的最新进展。我们的目的也是提供一个完整的概述，有助于强调选择特定药理特性所需的特征。
已经鉴定出两种不同的哺乳动物 SphK 同工型，SphK1 和 SphK2。这些同工型由不同的基因编码，表现出不同的亚细胞定位、生化特性和功能。SphK1 和 SphK2 的抑制在不同的病理条件下可能是有用的。
SphK1 和 SphK2 有许多共同的特征，但具有不同甚至相反的生物学功能。因此，几个研究小组有兴趣了解 SphKs 的选择性或非选择性抑制剂的治疗用途。此外，已经证明了两种同工型的代偿机制，从而导致了双重抑制剂的开发。
