Sphingosine-1-phosphate (S1P) is a pleiotropic signaling molecule that is synthesized intracellularly by two sphingosine kinase isoforms (SphK1, SphK2). S1P export is facilitated by two integral membrane proteins: MFSd2b and Spinster homolog 2 (Spns2). As a ligand to five G-protein coupled receptors (S1P1-5), S1P regulates a variety of cellular signaling pathways. For example, S1P is a chemoattractant that influences immune cell positioning. It is critical for proper lymphocyte egress from secondary lymphoid tissues into efferent lymph. Indeed, S1P1 receptor agonists, which are drugs marketed for multiple sclerosis treatment, suppress immune function by masking lymphocytes to the S1P-rich environment of lymph. Mouse genetic studies suggest that lymph endothelium Spns2 is responsible maintaining lymph S1P concentrations. Thus, an alternative therapeutic strategy is to inhibit Spns2, which might recapitulate the efficacy of S1P1 receptor modulators without the attendant adverse events common to that class. To this end, we report a structure-activity relationship (SAR) study of Spns2 inhibitors. Our medicinal chemistry campaign identified compound 16d, which contains a ‘lipid tail’ and a terminal ammonium head group reminiscent of S1P. In vitro studies in HeLa cells demonstrated that 16d inhibited Spns2 mediated S1P release into media. 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. Furthermore, Spns2 inhibitors were found to be protective against kidney fibrosis in the unilateral ischemia reperfusion injury model as well as in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Taken together, our studies suggest that Spns2 is a potential drug target.

Structure-activity relationship studies and in vivo activity of sphingosine-1-phosphate transporter spns2

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ACS Fall 2022

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