title: Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors.
abstract: Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1.
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Molly D
authors: MD
authors: Congdon
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Elizabeth S
authors: ES
authors: Childress
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Neeraj N
authors: NN
authors: Patwardhan
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: James
authors: J
authors: Gumkowski
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Emily A
authors: EA
authors: Morris
authors: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors: Yugesh
authors: Y
authors: Kharel
authors: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors: Kevin R
authors: KR
authors: Lynch
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: santosw@vt.edu.
authors: Webster L
authors: WL
authors: Santos
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011759:Pyrrolidines; C000608372:SLR080811; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase
keywords: S1P; SphK1; SphK2; Sphingosine kinase; Sphingosine-1-phosphate