Discovery of In Vivo Active Sphingosine-1-phosphate Transporter (Spns2) Inhibitors

Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five G-protein-coupled receptors (S1P1-5) to regulate cellular signaling pathways. S1P export is facilitated by Mfsd2b and spinster homologue 2 (Spns2). While mouse genetic studies suggest that Spns2 functions to maintain lymph S1P, Spns2 inhibitors are necessary to understand its biology and to learn whether Spns2 is a viable drug target. Herein, we report a structure-activity relationship study that identified the first Spns2 inhibitor 16d (SLF1081851). In vitro studies in HeLa cells demonstrated that 16d inhibited S1P release with an IC50 of 1.93 mu M. Administration of 16d to mice and rats drove significant decreases in circulating lymphocyte counts and plasma S1P concentrations, recapitulating the phenotype observed in mice made deficient in Spns2. Thus, 16d has the potential for development and use as a probe to investigate Spns2 biology and to determine the potential of Spns2 as a drug target.

Automated summary

In this study, the researchers identified a novel Spns2 inhibitor called 16d, which effectively inhibits the release of S1P. In addition, administration of 16d in mice and rats replicated the phenotype observed in Spns2-deficient mice. This study provides a new research tool for further understanding the biological function of Spns2 and evaluating its potential as a drug target.