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Consequences of S1P Transporter Inhibition
Webster L. Santos1, Ariel Burgio1, Shinji Tanaka3, Yugesh Kharel2, Tao Huang2, Mark Okusa3, and Kevin R. Lynch21 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 Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA 22903, USA.
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five native G-protein coupled receptors (S1P1-5) to regulate cell growth, survival, and proliferation. S1P has been implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis. In principle, S1P mediated signaling can be interdicted at the point of synthesis via sphingosine kinase, transport via Spns2 or mfsd2b, or at the receptor sites. Indeed, one node in the sphingosine-1-phosphate (S1P) pathway – the S1P1 receptor – is targeted by four marketed drugs for the treatment of multiple sclerosis and ulcerative colitis. Studies of these drugs revealed that S1P gradients are important in the positioning of immune cells, specifically the egress of T-lymphocytes from secondary lymphoid tissues. Targeting an S1P exporter (Spns2) that is ‘upstream’ of S1P receptor engagement is an alternate strategy that might recapitulate the efficacy of S1P receptor modulators without cardiac toxicity. In this presentation, we will discuss a complementary node of blocking S1P transport via genetic and pharmacological avenues. Our studies documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. We found that S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via Spns2. When bound to S1P1 expressed in perivascular cells, production of proinflammatory cytokines/chemokines upon injury was enhanced, leading to immune cell infiltration and subsequent fibrosis. To investigate the therapeutic potential of inhibiting Spns2, we performed a medicinal chemistry campaign and discovered SLB1122168 (IC50 = 94 ± 6 nM) as a potent inhibitor of Spns2-mediated S1P release. Administration of SLB1122168 to mice and rats resulted in a dose-dependent decrease in circulating lymphocytes, a pharmacodynamic indication of Spns2 inhibition. The discovery of SLB1122168 provides a valuable tool compound to explore both the therapeutic potential of targeting Spns2 and the physiologic consequences of selective S1P export inhibition.
We thank that National Institutes of Health (R01 AI144026) for funding.