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

ABSTRACT: 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 μM. Administration of 16d to mice and rats drove significant decreases in circulating lymphocyte counts and plasma S1P concent

SUBMITTER: Fritzemeier R 

PROVIDER: S-EPMC9733493 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature