Elsevier

Pharmacological Research

Volume 113, Part A, November 2016, Pages 521-532
Pharmacological Research

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

https://doi.org/10.1016/j.phrs.2016.09.025Get rights and content

Abstract

Sphingosine 1-phosphate (S1P) 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 S1P receptors, primarily on S1P receptor 1 (S1P1). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P 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 S1P1-modulators, there has been considerable effort in targeting other components of the S1P 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 S1P signaling.

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.

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