To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling

Sphingosine 1-phosphate (SIP) is an extracellular lipid signaling molecule that acts as a selective, high affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on SIP receptors, primarily on SIP receptor 1 (S1P(1)). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation SIP receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P(1)-modulators, there has been considerable effort in targeting other components of the SIP signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting SIP signaling. (C) 2016 Elsevier Ltd. All rights reserved.