Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.
Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.
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DOI：
10.1021/acs.jmedchem.7b00233
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发表时间：
2017-05-11
影响因子：
7.3
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Childress ES;Kharel Y;Brown AM;Bevan DR;Lynch KR;Santos WL
sphingosin 1-phosphate （S1P）是一种多效性信号分子，可与其5个g蛋白偶联受体S1P1-5相互作用，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。鞘氨酸激酶（SphK）异构体1和2作为S1P合成的关键介质，作为药物抑制的可行靶点而受到关注。在这篇报道中，我们描述了SphK氨基噻唑类胍类抑制剂的设计、合成和生物学评价。令人惊讶的是，结合已报道的SphK1抑制剂的特点，产生了SphK1/2双抑制剂20l (SLC4011540) （hSphK1 Ki = 120 nM, hSphK2 Ki = 90 nM）和SphK2抑制剂20dd (SLC4101431) （Ki = 90 nM， SphK2选择性100倍）。这些化合物可有效降低体外S1P水平。体内给药20dd证实抑制SphK2可增加血中S1P水平。
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors S1P1-5 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 report, 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 Ki = 120 nM, hSphK2 Ki = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (Ki = 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.
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影响因子：
2.7
作者：
Leroux FR;Manteau B;Vors JP;Pazenok S
通讯作者：
Pazenok S
影响因子：
7.3
作者：
Baek DJ;MacRitchie N;Anthony NG;Mackay SP;Pyne S;Pyne NJ;Bittman R
通讯作者：
Bittman R
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
DOI：
10.1124/jpet.115.225862
发表时间：
2015-10-01
影响因子：
3.5
作者：
Kharel, Yugesh;Morris, Emily A.;Lynch, Kevin R.
通讯作者：
Lynch, Kevin R.
影响因子：
7.3
作者：
Aurelio, Luigi;Scullino, Carmen V.;Flynn, Bernard L.
通讯作者：
Flynn, Bernard L.