Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors.
Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors.
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DOI：
10.1016/j.bmc.2020.115941
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发表时间：
2021-01-15
影响因子：
3.5
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Li H;Sibley CD;Kharel Y;Huang T;Brown AM;Wonilowicz LG;Bevan DR;Lynch KR;Santos WL
鞘氨醇1-磷酸（S1 P）信号通路是一个有吸引力的目标，药理学操作，由于其参与癌症的进展和免疫细胞的趋化性。S1 P的合成由鞘氨醇激酶1或2（SphK 1或SphK 2）对鞘氨醇和ATP的作用催化。虽然已经报道了SphK 1或SphK 2的有效和选择性抑制剂，但仍然需要开发有效的双重SphK 1/SphK 2抑制剂。为此，我们报告了2-（羟甲基）吡咯烷基抑制剂的构效关系分析，其中22 d是本系列中报道的最有效的双重SphK 1/SphK 2抑制剂（SphK 1 Ki = 0.679 μM，SphK 2 Ki = 0.951 μM）。22 d抑制工程酿酒酵母的生长，并降低组织细胞性淋巴瘤髓样细胞系（U937细胞）中的S1 P水平，表明体外抑制SphK 1和2。对SphK 1和SphK 2的Sph结合口袋内停靠的22 d的分子模拟研究表明，2-（羟甲基）吡咯烷头之间的必要氢键与ATP结合口袋附近的天冬氨酸和丝氨酸残基相互作用，这为双重抑制提供了基础。此外，十二烷基尾采用了在与SphK 1结合的鞘氨醇的晶体结构中发现的“J形”构象。总的来说，这些研究提供了深入了解SphK 1和2活性位点的分子间相互作用，以实现最大的双重抑制活性。
The sphingosine 1-phosphate (S1P) signaling pathway is an attractive target for pharmacological manipulation due to its involvement in cancer progression and immune cell chemotaxis. The synthesis of S1P is catalyzed by the action of sphingosine kinase 1 or 2 (SphK1 or SphK2) on sphingosine and ATP. While potent and selective inhibitors of SphK1 or SphK2 have been reported, development of potent dual SphK1/SphK2 inhibitors are still needed. Towards this end, we report the structure–activity relationship profiling of 2-(hydroxymethyl)pyrrolidine-based inhibitors with 22d being the most potent dual SphK1/SphK2 inhibitor (SphK1 Ki = 0.679 μM, SphK2 Ki = 0.951 μM) reported in this series. 22d inhibited the growth of engineered Saccharomyces cerevisiae and decreased S1P levels in histiocytic lymphoma myeloid cell line (U937 cells), demonstrating inhibition of SphK1 and 2 in vitro. Molecular modeling studies of 22d docked inside the Sph binding pocket of both SphK1 and SphK2 indicate essential hydrogen bond between the 2-(hydroxymethyl)pyrrolidine head to interact with aspartic acid and serine residues near the ATP binding pocket, which provide the basis for dual inhibition. In addition, the dodecyl tail adopts a “J-shape” conformation found in crystal structure of sphingosine bound to SphK1. Collectively, these studies provide insight into the intermolecular interactions in the SphK1 and 2 active sites to achieve maximal dual inhibitory activity.
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影响因子：
25.7
作者：
Li, Changyong;Kong, Yaxian;Li, Liying
通讯作者：
Li, Liying
影响因子：
4.1
作者：
Schnute, Mark E.;McReynolds, Matthew D.;Nagiec, Marek M.
通讯作者：
Nagiec, Marek M.
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