Etrasimod, a Selective S1P1,4,5 Receptor Modulator, Exhibits Differential G Protein Signaling Compared to Other S1P Receptor Modulators

Abstract

BackgroundEtrasimod (APD334) is an oral, selective sphingosine‐1‐phosphate (S1P) receptor modulator in development for atopic dermatitis and inflammatory bowel disease. In humans, S1P receptor modulators decrease heart rate at first‐dose due to initial on‐target S1P receptor 1 (S1P1) agonism in cardiac tissue. S1P1 agonism activates Gi and β‐arrestin signaling pathways: β‐arrestin activation leads to receptor internalization, the proposed mechanism by which S1P receptor modulators regulate lymphocyte trafficking; Gi‐coupled signaling activates G‐protein coupled inwardly rectifying potassium (GIRK) channels, that may contribute to the regulation of heart rate. Approved or investigational S1P receptor modulators have demonstrated different degrees of heart rate reduction and atrioventricular block in clinical studies. Such differences may be the result of differential signaling through the Gi coupled GIRK pathway.AimTo investigate S1P receptor expression in human sinoatrial (SA) node tissue, and the relative S1P1 mediated signaling events and GIRK channel activation of etrasimod and other S1P receptor modulators in the context of first dose heart rate effects.MethodsS1P receptor profiling was performed by qPCR in normal human primary SA node and right atrium samples. Potencies for multiple S1P receptor modulators to activate different S1P1 downstream signaling pathways (GTPγS, cAMP, β‐arrestin, S1P1 internalization) were measured in recombinant human‐S1P1 expressing cells. Gi mediated inhibition of cAMP was also measured in primary HUVEC. GIRK channel activation was measured in isolated adult human primary atrial myocytes.ResultsProfiling of S1P receptors in normal human atrial tissue and SA node demonstrated enriched expression of S1P1,2,3 with only minor expression of S1P4,5. Etrasimod was equipotent to other S1P receptor‐ modulators such as ozanimod, fingolimod, and siponimod in promoting β‐arrestin recruitment and S1P1 receptor internalization. Etrasimod was significantly less potent than ozanimod, fingolimod, and siponimod in assays measuring G‐protein activation (GTPγS binding and cAMP inhibition). In comparisons of GIRK activation, etrasimod was found to be a less potent activator of human atrial GIRK channels than ozanimod.ConclusionsWhen compared to other S1P1 modulators, the pharmacological profile of etrasimod at the S1P1 receptor suggests diminished capacity for signaling through Gi‐protein dependent pathways believed to be responsible for transient reductions in heart rate, while maintaining potent signaling in the β‐arrestin recruitment and receptor internalization related pathways underpinning the therapeutic efficacy of S1P1 modulators in immune‐mediated inflammatory disease settings.Support or Funding InformationThe study was sponsored by Arena Pharmaceuticals, Inc.