Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22904, United States.
J Med Chem. 2011 May 26;54(10):3524-48. doi: 10.1021/jm2001053. Epub 2011 May 2.
Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.
鞘氨醇 1-磷酸（S1P）是一种生物活性脂质，已被确定为癌症进展的加速剂。鞘氨醇激酶（SphKs）是 S1P 的唯一产生者，因此，SphK 抑制剂可能在癌症缓解和化疗增敏方面有效。在两种 SphK 中，SphK1 的过表达已在许多癌细胞系和组织中观察到，并被认为是推定的靶标，而不是特征较差的 SphK2。本文介绍了基于脒的纳摩尔级 SphK1 亚型选择性抑制剂的设计和合成。然后，使用该脒抑制剂文库训练 SphK1 的同源模型，以预测其他更有效抑制剂的活性。最后，在人白血病 U937 细胞中验证了选择的脒抑制剂，它们在纳摩尔浓度下显著降低了内源性 S1P 水平。
