Structure guided design of a series of sphingosine kinase (SphK) inhibitors

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• 作者：Darin J. Gustin ; Yihong Li ; Matthew L. Brown ; Xiaoshan Min ; Mike J. Schmitt ; Malgorzata Wanska ; Xiaodong Wang ; Richard Connors ; Sheere Johnstone ; Mario Cardozo ; Alan C. Cheng ; Shawn Jeffries ; Brendon Franks ; Shyun Li ; Shanling Shen ; Mariwil Wong ; Holger Wesche ; Guifen Xu ; Timothy J. Carlson ; Matthew Plant ; et al.
• 关键词：Sphingosine kinase 1 inhibitor ; Sphingosine kinase 2 inhibitor ; Murine SphK ; Structure based ; Drug design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 August, 2013
• 年：2013
• 卷：23
• 期：16
• 页码：4608-4616
• 全文大小：3004 K

文摘

Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other¡¯s loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (?/?) mice.