Sphingosine kinase inhibitors: a review of patent literature (2006-2015).
Sphingosine kinase inhibitors: a review of patent literature (2006-2015).
复制标题
鞘氨酸激酶抑制剂：专利文献综述（2006- 2015年）。
DOI：
10.1080/13543776.2016.1226282
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发表时间：
2016-12
影响因子：
6.6
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Lynch KR;Thorpe SB;Santos WL
鞘氨醇激酶（SphK 1和SphK 2）是多效脂质介质鞘氨醇-1-磷酸（S1 P）的唯一来源。S1 P与多种疾病有关，如癌症、阿尔茨海默病、镰状细胞病和纤维化，因此S1 P的生物合成途径是药物发现的逻辑目标。在这篇综述中，作者考虑了2006-2016 Q1的SphK抑制剂专利文献，重点是物质组合物实用专利。使用检索词“鞘氨醇和激酶”查询Espacenet数据库，以识别相关文献。早期的抑制剂发现集中在SphK 1上，偏向于肿瘤适应症。在结构上，所报道的抑制剂占据了鞘氨醇的“J形”结合口袋。改进的SphK 1抑制剂缺乏细胞毒性，这引起了人们对该酶作为肿瘤学靶点的怀疑。SphK 2抑制剂在最近的专利申请中有特色。有趣的是，SphK 1和SphK 2抑制和基因“敲除”对循环S1 P水平具有相反的影响：SphK 1抑制/基因消融降低，而SphK 2抑制/基因消融增加，血液S1 P。随着对S1 P生理作用的了解的增加和更多药物样SphK抑制剂的出现，抑制一种或两种SphK同种型可以为治疗疾病提供独特的策略。
Sphingosine kinase (SphK1 & SphK2) is the sole source of the pleiotropic lipid mediator, sphingosine-1-phosphate (S1P). S1P has been implicated in a variety of diseases such as cancer, Alzheimer’s disease, sickle cell disease and fibrosis and thus the biosynthetic route to S1P is a logical target for drug discovery. In this review, the authors consider the SphK inhibitor patent literature from 2006–2016 Q1 with the emphasis on composition of matter utility patents. The Espacenet database was queried with the search term “sphingosine AND kinase” to identify relevant literature. Early inhibitor discovery focused on SphK1 with a bias towards oncology indications. Structurally, the reported inhibitors occupy the sphingosine ‘J-shaped’ binding pocket. The lack of cytotoxicity with improved SphK1 inhibitors raises doubt about the enzyme as an oncology target. SphK2 inhibitors are featured in more recent patent applications. Interestingly, both SphK1 and SphK2 inhibition and gene ‘knockout’ share opposing effects on circulating S1P levels: SphK1 inhibition/gene ablation decreases, while SphK2 inhibition/gene ablation increases, blood S1P. As understanding of S1P’s physiological roles increases and more drug-like SphK inhibitors emerge, inhibiting one or both SphK isotypes could provide unique strategies for treating disease.