Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.
Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.
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DOI：
10.1021/acsbiomedchemau.2c00017
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发表时间：
2022-10-19
期刊：
影响因子：
--
通讯作者：
Santos, Webster L.
中科院分区：
文献类型：
--
作者：
Pashikanti, Srinath;Foster, Daniel J.;Kharel, Yugesh;Brown, Anne M.;Bevan, David R.;Lynch, Kevin R.;Santos, Webster L.
关键词：
1-磷酸鞘氨醇(S1P)是一种多效性信号分子，它与5个天然的G蛋白偶联受体(S1P1-5)相互作用，调节细胞的生长、存活和增殖。S1P参与了多种病理过程，包括癌症、肾脏纤维化和多发性硬化症。SphK亚型1和2作为S1P合成的关键介导物，作为药物干预的有效靶点而备受关注。在这份报告中，我们描述了鞘氨醇激酶2(SphK2)抑制剂的设计、合成和生物学评价，重点是系统地在现有SphK2抑制剂的脂类尾部引入刚性结构。实验和分子模拟研究表明，构象受限的“亲脂尾”类似物具有巨大的末端部分或内部的苯环，有助于补充SphK2的“J”形鞘氨醇结合口袋。我们确定14c(SLP9101555)是一种有效的SphK2抑制剂(Ki=90 nM)，其选择性是SphK1的200倍。分子对接研究表明了关键的相互作用：环己基环结合在口袋深处的裂隙中，三氟甲基适合于一个小的侧腔，以及胍基和Asp308之间的氢键(氨基酸编号指的是人类SphK2(异构体c)直系物)。使用U937人组织细胞淋巴瘤细胞进行的体外研究显示，我们的SphK2抑制剂显著降低了细胞外S1P水平。给小鼠注射14c(剂量：5 mg/kg)后，循环中S1P水平持续升高，提示靶向参与。
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five native G-protein coupled receptors (S1P1–5) to regulate cell growth, survival, and proliferation. S1P has been implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis. As key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmacologic intervention. In this report, we describe the design, synthesis, and biological evaluation of sphingosine kinase 2 (SphK2) inhibitors with a focus on systematically introducing rigid structures in the aliphatic lipid tail present in existing SphK2 inhibitors. Experimental as well as molecular modeling studies suggest that conformationally restricted “lipophilic tail” analogues bearing a bulky terminal moiety or an internal phenyl ring are useful to complement the “J”-shaped sphingosine binding pocket of SphK2. We identified 14c (SLP9101555) as a potent SphK2 inhibitor (Ki = 90 nM) with 200-fold selectivity over SphK1. Molecular docking studies indicated key interactions: the cyclohexyl ring binding in the cleft deep in the pocket, a trifluoromethyl group fitting in a small side cavity, and a hydrogen bond between the guanidino group and Asp308 (amino acid numbering refers to human SphK2 (isoform c) orthologue). In vitro studies using U937 human histiocytic lymphoma cells showed marked decreases in extracellular S1P levels in response to our SphK2 inhibitors. Administration of 14c (dose: 5 mg/kg) to mice resulted in a sustained increase of circulating S1P levels, suggesting target engagement.
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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
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB
影响因子：
4.1
作者：
Kharel, Yugesh;Huang, Tao;Lynch, Kevin R.
通讯作者：
Lynch, Kevin R.
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：
Sibley CD;Morris EA;Kharel Y;Brown AM;Huang T;Bevan DR;Lynch KR;Santos WL
通讯作者：
Santos WL