How S1P Works
S1P is synthesized by all cells in the body but only some cell types such as endothelial cells release S1P to the extracellular space, where gains access to cell surface S1P receptors. The S1P1 receptor, which is the receptor isoform common to all SRM drugs, is expressed ubiquitously leading to a set of on-target adverse events. Blocking the selectively-expressed S1P transporters, which reshapes S1P gradients, affords the subtler strategy of modulating this biochemical pathway.
S1P1R
Existing drugs act here to block S1P receptor (S1P1R) signaling (immunosupressive)
SPNS2
S1PTx’s experimental drugs act here to block S1P export (SPNS2) (immunomodulatory)
How S1P Works
S1P is synthesized by all cells in the body but only some cell types such as endothelial cells release S1P to the extracellular space, where gains access to cell surface S1P receptors. The S1P1 receptor, which is the receptor isoform common to all SRM drugs, is expressed ubiquitously leading to a set of on-target adverse events. Blocking the selectively-expressed S1P transporters, which reshapes S1P gradients, affords the subtler strategy of modulating this biochemical pathway.
Science
Approved Drugs in the S1P Pathway have On-target Liabilities
The recognition that S1P is required for correct lymphocyte cell trafficking ultimately resulted in S1P receptor modulator drugs (SRMs) for autoimmune diseases. While these medicines validate the S1P pathway as a drug target, SRMs are broadly immunosuppressive, cause initial dose bradycardia and compromise endothelial barrier integrity.
S1P
Sphingosine 1-phosphate (S1P) is key to maintaining endothelial barrier integrity.
The S1P Therapeutics Approach: Re-Shaping S1P Gradients
The on-target labilities of SRM drugs illustrate the need for safer drugs to modulate lymphocyte trafficking. S1P Therapeutics is targeting SPNS2-dependent S1P transporters, which shape S1P gradients, to realize such a drug. Our studies reveal that our proprietary SPNS2 inhibitors are less broadly immunosuppressive than SRMs with less adverse events.