2. Academic Validation
  3. Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors

Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors

  • Bioorg Med Chem Lett. 2015 Nov 1;25(21):4956-4960. doi: 10.1016/j.bmcl.2015.03.041.
Molly D Congdon 1,  Elizabeth S Childress 1,  Neeraj N Patwardhan 1,  James Gumkowski 1,  Emily A Morris 1,  Yugesh Kharel 2,  Kevin R Lynch 2,  Webster L Santos 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
  • 2 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
  • 3 Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: [email protected].
PMID: 25862200 DOI: 10.1016/j.bmcl.2015.03.041
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.

Keywords

S1P; SphK1; SphK2; Sphingosine kinase; Sphingosine-1-phosphate.

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