Invited reviewTo fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling
Graphical abstract
Section snippets
S1P metabolism and signaling
Sphingosine 1-phosphate (S1P) is a structurally simple, phosphorylated monoacyl lipid with a well-defined metabolic pathway. It is generated by the activity of sphingosine kinase by phosphorylating sphingosine at the C1 position [1] (Fig. 1). This can be reversed through dephosphorylation by two specific S1P phosphatases (SGPP1 and SGPP2) [2], [3] or by one of several promiscuous lipid phosphate phosphatases (PLPP1-PLPP3) [4]. Alternatively, S1P can be irreversibly degraded by a single gene
Drug candidates and lead compounds targeting S1P receptors
For a number of reasons, the majority of drug development efforts targeting S1P signaling have been directed at the S1P receptors rather than the ligand or its metabolic pathway. 1) GPCRs are highly druggable. GPCRs are highly diverse, cell surface receptors that mediate fundamental processes in virtually all cell types. As a result, GPCRs make up the largest family of targets for drugs currently in clinical use, representing ∼20% of drug-binding proteins [14]. 2) The actions of S1P are
Drug candidates and lead compounds targeting S1P metabolism
Due to the relatively simple and well-defined metabolic pathway regulating S1P, the enzymes in this pathway represent attractive targets for pharmacological manipulation of S1P levels. This would then allow the modulation of global S1P signaling. Although this has the inherent disadvantage of limited specificity—affecting the activity of all five S1P receptors— this approach becomes an advantage when targeting processes in which multiple S1P receptors contribute to a biological effect with
Sonepcizumab (ASONEP/iSONEP)
A novel approach to global attenuation of S1P signaling involves ligand sequestration with a mAb, similar to the approach taken with the successful anti-VEGF therapeutic mAb, bevacizumab [139]. To that end, Lpath Therapeutics (San Diego, CA, U.S.A.) generated a murine mAb (LT1002) that selectively binds S1P [140]. It was shown to inhibit tumor growth and angiogenesis in a number of in vivo models for different cancer types [141], and demonstrated efficacy in animal models for ophthalmic
Conclusions and implications for continued drug development
Since the discovery that S1P acts as a high-affinity ligand for a family of GPCRs, the field of sphingolipid biology has become a robust discipline that has revealed the involvement of S1P-mediated signaling pathways in nearly every mammalian physiological system. S1P receptor activity influences fundamental cellular processes in the immune system, nervous system, cardiovascular system, reproductive system, and skeletal system. It is unsurprising, then, that dysregulation of S1P signaling has
Acknowledgements
This work was supported by the Ministry of Education, Singapore (DRH), and the National University of Singapore (DRH). DRH has an equity position in Expression Drug Designs, LLC.
References (174)
Regulation of sphingosine kinase and sphingolipid signaling
Trends Biochem. Sci.
(2011)- et al.
Characterization of murine sphingosine-1-phosphate phosphohydrolase
J. Biol. Chem.
(2002) - et al.
Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hspp2
J. Biol. Chem.
(2003) - et al.
Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease
Cell. Signal.
(2009) - et al.
Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast
Biochem. Biophys. Res. Commun.
(1998) - et al.
Lysophospholipids and their receptors in the central nervous system
Biochim. Biophys. Acta
(2013) - et al.
Analysis of the mode of action of a novel immunosuppressant fty720 in mice
Immunopharmacology
(1999) - et al.
The immunosuppressant fty720 is phosphorylated by sphingosine kinase type 2
FEBS Lett.
(2003) - et al.
Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor
J. Biol. Chem.
(2007) - et al.
An effect of fty720 on acute rejection in canine renal transplantation
Transplant. Proc.
(1998)