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 (SLF1081851). In vitro studies in HeLa cells demonstrated that inhibited S1P release with an IC of 1.93 μM. Administration of 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, 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.