Molecular Pharmacology of Sphingosine 1-Phosphate

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Until recently, the lipid mediator sphingosine 1-phosphate (S1P) was viewed as a cell survival, motility and mitogenic factor. Therefore, S1P receptor antagonists were regularly imagined to be useful as anti-cancer drugs. Ironically, it was the discovery that S1P receptor agonists - acting to modulate the immune system by disrupting lymphocyte trafficking - that validated S1Psignaling systems as bone fide drug targets. Indeed, the spectacular success of the first-in-class investigational drug, FTY720, has fundamentally and profoundly altered the 81P landscape. FTY720 is in phase III clinical trials for kidney transplantation and multiple sclerosis and patients are being recruited for a phase II trial for senile dementia. Nevertheless, much remains to be learned about fingolimods (sphingosine analogs that modulate the immune response, e.g. FTY720) - the structure activity relationship (SAR) of fingolimods (pro-forms and active compounds), the S1P receptor types whose activation is necessary for efficacy in various disease models, the nature of the inactivating phosphatase(s), definition of possible non-receptor targets and the need to eliminate known toxicities. Thus our experimental plan can be stated succinctly as discovering additional new chemical entities to enable development of receptor selective agonists and antagonists (and their pro-drugs), assessment of whether S1P1 receptor agonists act as functional antagonists, identification of the inactivating phosphatases and assessment of two non-receptor targets, the enzymes S1P lyase and autotaxin. The strength of our program remains its combination of synthetic chemistry, genetic models and molecular pharmacology. In the past cycle of funding, we synthesized selective S1P receptor agonists and their pro-forms as well as the first S1P receptor antagonist. Further, we discovered that sphingosine kinase type 2 is the activating enzyme for FTY720 and most other fingolimods. Minimally, our continued efforts will extend dramatically the SAR of compounds active at S1P receptors, phosphotases, sphingosine kinases and S1P lyase. Optimally, our work will lead to the increased understanding of a new class of oral medications for autoimmune disease such as multiple sclerosis, inflammatory bowel diseases andtype I diabetes - indeed our current compounds have already contributed to this knowledge base. Further, we will use these tool compounds to determine whether such therapeutic agents could be useful in treating renal failure, vascular injury, atherosclerosis, cancer and other pathologies.