Development of small-molecule inhibitors of sphingosine-1-phosphate signaling.
Development of small-molecule inhibitors of sphingosine-1-phosphate signaling.
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DOI：
10.1016/j.pharmthera.2011.08.004
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发表时间：
2011-12
影响因子：
13.5
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Edmonds, Yvette;Milstien, Sheldon;Spiegel, Sarah
关键词：
鞘氨醇是一种多功能神经鞘糖脂介体，在细胞内由两种鞘氨醇激酶同工酶SphK1和SphK2产生，调节许多细胞和生理过程，对动态平衡和发育以及病理生理学非常重要。S1P的许多作用是由一组普遍存在的、特异表达的五种特定细胞表面受体介导的，尽管最近也发现了S1P的重要直接细胞内靶点。S1P、SphK1和/或S1P受体与许多疾病的发生和发展有关，包括许多类型的癌症，特别是炎症性疾病，如多发性硬化症、哮喘、类风湿性关节炎、炎症性肠道疾病和脓毒症。S1P的形成和信号转导是开发新的治疗药物的诱人靶点。一些SphKs和S1PR抑制剂的效果已经在人类疾病的动物模型中进行了检验。免疫抑制剂FTY720(称为Fingolomod或Gilenya)最近被批准用于治疗多发性硬化症，其作用通过下调S1PR1介导，已成为以S1P为中心的药物的黄金标准。在这里，我们综述S1P生物学和信号转导，重点是特定干预措施的潜在治疗益处，并讨论针对特定S1P受体亚型和SphKs抑制剂的小分子拮抗剂和激动剂的最新发展。
The pleiotropic sphingolipid mediator, sphingosine-1-phosphate, produced in cells by two sphingosine kinase isoenzymes, SphK1 and SphK2, regulates many cellular and physiological processes important for homeostasis and development and pathophysiology. Many of the actions of S1P are mediated by a family of five specific cell surface receptors that are ubiquitously and specifically expressed, although important direct intracellular targets of S1P have also recently been identified. S1P, SphK1, and or S1P receptors have been linked to onset and progression of numerous diseases, including many types of cancer, and especially inflammatory disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, and sepsis. S1P formation and signaling are attractive targets for development of new therapeutics. The effects of a number of inhibitors of SphKs and S1PRs have been examined in animal models of human diseases. The effectiveness of the immunosuppressant FTY720 (known as Fingolomod or Gilenya), recently approved for the treatment of multiple sclerosis, whose actions are mediated by downregulation of S1PR1, has become the gold standard for S1P-centric drugs. Here, we review S1P biology and signaling with an emphasis on potential therapeutic benefits of specific interventions and discuss recent development of small molecule antagonists and agonists that target specific subtypes of S1P receptors as well as inhibitors of SphKs.
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
5.8
作者：
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通讯作者：
Liu X
DOI：
10.1158/1078-0432.ccr-10-2323
发表时间：
2011-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dickson MA;Carvajal RD;Merrill AH Jr;Gonen M;Cane LM;Schwartz GK
通讯作者：
Schwartz GK
影响因子：
--
作者：
Kitano, M;Hla, T;Sano, H
通讯作者：
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影响因子：
3.3
作者：
Kanno, T.;Nishizaki, T.;Nakamura, S.
通讯作者：
Nakamura, S.