Childress Elizabeth S, Kharel Yugesh, Brown Anne M, Bevan David R, Lynch Kevin R, Santos Webster L
Department of Pharmacology, University of Virginia , Charlottesville, Virginia 22908, United States.
J Med Chem. 2017 May 11;60(9):3933-3957. doi: 10.1021/acs.jmedchem.7b00233. Epub 2017 Apr 25.
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P) to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK. Surprisingly, combining features of reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 K = 120 nM, hSphK2 K = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (K = 90 nM, 100-fold SphK2 selectivity). These compounds effectively decrease S1P levels in vitro. In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels.
鞘氨醇-1-磷酸（S1P）是一种多效性信号分子，它与其五种G蛋白偶联受体相互作用以调节细胞生长和存活，并与包括癌症和镰状细胞病在内的多种疾病有关。作为S1P合成中的关键介质，鞘氨醇激酶（SphK）亚型1和2作为药物抑制的可行靶点已引起关注。在本文中，我们描述了基于氨基噻唑的SphK胍类抑制剂的设计、合成及生物学评价。令人惊讶的是，结合已报道的SphK1抑制剂的特征产生了SphK1/2双重抑制剂20l（SLC4011540）（人SphK1的K = 120 nM，人SphK2的K = 90 nM）和SphK2抑制剂20dd（SLC4101431）（K = 90 nM，对SphK2的选择性为100倍）。这些化合物在体外有效降低S1P水平。体内给予20dd证实抑制SphK2会增加血液中的S1P水平。
