Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors. (15th January 2021)

• Record Type: Journal Article
• Authors: Li, Hao; Sibley, Christopher D.; Kharel, Yugesh; Huang, Tao; Brown, Anne M.; Wonilowicz, Laura G.; Bevan, David R.; Lynch, Kevin R.; Santos, Webster L.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 30(2021)
• Publication Date: 2021-01-15
• Subjects: Sphingosine kinase -- SphK1 -- Inhibitor -- Sphingosine -- Sphingosine 1-phosphate -- Lipophilic binding pocket -- PF-543 -- Structure-activity relationship; S1P Sphingosine 1-phosphate -- Sph Sphingosine -- SphK Sphingosine kinase -- HCTU O-(1H-6-chlorobenzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115941
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 K i = 0.679 μM, SphK2 K i = 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.