SCIENCE

Sphingosine 1-phosphate (S1P) is a chemotactic lipid that functions to control immune cell positioning, to maintain endothelial barrier integrity, and to influence extracellular matrix remodeling.  S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. Extracellular S1P is a ligand for a set of  G-protein coupled receptors (S1P1-5). In particular, agonist ligand binding to S1P1 results in receptor internalization and thus blocks lymphocyte egress from lymph nodes to efferent lymph. This property is the mechanism of action of S1P receptor modulators (SRMs), which are immunomodulatory drugs that are approved therapies for management of multiple sclerosis and ulcerative colitis. Unfortunately, initial dose bradycardia is an adverse effect of the SRM drug class.  An alternate therapeutic strategy is to re-shape the S1P concentration gradients by selective blockade of S1P transport. S1P Therapeutics has proprietary inhibitors of S1P transport that capture the efficacy of SRMs with less toxicities. These S1P transport modulators (STMs) are being developed as potential treatments of inflammatory and fibrotic diseases.