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Functional Activity of Etrasimod and a Diverse Panel of Sphingosine‐1‐Phosphate Receptor (S1PR1) Modulators at S1P4 Receptors
Author(s) -
Adams John W,
Unett David J,
Chen Xiaohua,
Gaidarov Ibragim
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.993.12
Subject(s) - s1pr1 , sphingosine 1 phosphate receptor , internalization , fingolimod , receptor , sphingosine 1 phosphate , g protein coupled receptor , sphingosine kinase , sphingosine , pharmacology , signal transduction , microbiology and biotechnology , biology , chemistry , biochemistry , cancer research , immunology , multiple sclerosis , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
The S1P1 receptor modulator FTY720 (Fingolimod) exerts numerous anti‐inflammatory effects at least in part by producing sustained receptor internalization resulting in loss of cellular responsiveness to S1P. FTY720 and a number of next‐generation S1PR1 modulators also have varying degrees of activity at the S1PR4 and 5 receptor subtypes. Activity at S1PR5 has been suggested to be involved in the beneficial central effects of Fingolimod in multiple sclerosis. However, little is known about the nature of the interaction of these modulators with S1PR4. We sought to more thoroughly characterize the activity of a panel of structurally diverse S1PR4 modulators. FTY720 phosphate and a panel of S1P receptor modulators were evaluated for their abilities to interact with S1PR4 using a broad panel of functional assays designed to interrogate signaling pathways and receptor internalization. Compounds evaluated included Etrasimod (APD334), a novel S1PR modulator in clinical development, additional compounds that have undergone clinical investigation, and literature compounds reported to be S1PR4 selective. As observed with the S1P1 receptor, treatment of a S1PR4 expressing cell lines with FTY720 phosphate and structurally diverse S1PR1 modulators induced recruitment of b‐arrestin and drove rapid and robust receptor internalization. Label free Dynamic Mass Redistribution assays (Corning®, Epic®) readily detected S1PR4 mediated functional responses. Differential effects of S1P modulators on the kinetics of S1P4R internalization/recycling and persistence of signaling following drug removal were observed. Treatment with selected modulators affected the functional properties of S1PR4 expressing human dendritic cells. These data demonstrate that the pharmacology of S1PR modulators at S1PR4 largely mirrors that observed at S1PR1 and suggest that S1PR1 modulators with activity at S1PR4 may possess additional beneficial effects on immune modulation. Support or Funding Information Funding: Arena Pharmaceuticals, Inc.