Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism

Vogt, Dominik Walter; Stark, Holger

doi:10.1002/med.21402

Cited by 16 publications

(18 citation statements)

References 474 publications

(533 reference statements)

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“…Sphingolipids are integral components of cell membranes in the regulation of fluidity and lipid bilayer composition, organizing the assembly of signaling molecules, and protein trafficking. Particularly, some sphingolipids like sphingosine (Sph), sphingosine-1-phosphate (S1P), and ceramide (Cer) also act as bioactive signaling molecules and are responsible for the regulation of cell growth, differentiation, senescence, or apoptosis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency

et al. 2018

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BackgroundCongenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment.MethodsNineteen patients (14 women) with MS receiving oral fingolimod (Gilenya®, Novartis) therapy were included. Median age was 34.2 years (range; 21.3–44.6 years). Median duration of fingolimod treatment was 32 months (range; 6–52 months) at a dose of 0.5 mg/day. Basal and ACTH-stimulated adrenal steroid measurements were evaluated simultaneously employing LC-MS/MS based steroid panel. Basal steroid concentrations were also compared to that of sex- and age-matched healthy subjects. Cortisol and 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone were used to assess glucocorticoid, mineralocorticoid and sex steroid producing pathways, respectively.ResultsBasal ACTH concentrations of the patients were 20.8 pg/mL (6.8–37.8 pg/mL) (normal range; 5–65 pg/mL). There was no significant difference in the basal concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone between patients and controls (p = 0.11, 0.058, 0.74, 0.15; respectively). All patients showed adequate cortisol response to 250 mcg IV ACTH stimulation (243 ng/mL, range; 197–362 ng/mL). There was no significant correlation between duration of fingolimod treatment and basal or ACTH-stimulated cortisol or change in cortisol concentrations during ACTH stimulation test (p = 0.57, 0.66 and 0.21, respectively).ConclusionModification and inhibition of S1P lyase activity by the long-term therapeutic use of fingolimod is not associated with adrenal insufficiency in adult patients with MS. This suggests that S1P lyase has potentially a critical role on adrenal development rather than the function of a fully mature adrenal gland.

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Section: Introductionmentioning

confidence: 99%

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency

et al. 2018

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“…Research over the past two decades identified S1P as a potent bioactive lipid molecule that regulates various cellular processes including cell growth, apoptosis, immune regulation, etc. (4–9). …”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate: A Novel Target for Lung Disorders

Mohammed

Harikumar

2017

Front. Immunol.

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Sphingosine 1-phosphate (S1P) is involved in a wide range of cellular processes, which include proliferation, apoptosis, lymphocyte egress, endothelial barrier function, angiogenesis, and inflammation. S1P is produced by two isoenzymes, namely, sphingosine kinase 1 and 2 (SphK1 and 2) and once produced, S1P can act both in an autocrine and paracrine manner. S1P can be dephosphorylated back to sphingosine by two phosphatases (SGPP 1 and 2) or can be irreversibly cleaved by S1P lyase. S1P has a diverse range of functions, which is mediated in a receptor dependent, through G-protein coupled receptors (S1PR1–5) or receptor independent manner, through intracellular targets such as HDACs and TRAF2. The involvement of S1P signaling has been confirmed in various disease conditions including lung diseases. The SphK inhibitors and S1PR modulators are currently under clinical trials for different pathophysiological conditions. There is a significant effort in targeting various components of S1P signaling for several diseases. This review focuses on the ways in which S1P signaling can be therapeutically targeted in lung disorders.

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“…Other approaches have also been employed to manipulate S1P activity including targeting SphKs to control S1P synthesis. 3, 35–37 There are currently multiple reports of potent SphK1-selective inhibitors and SphK1/SphK2-dual inhibitors (Figure 1). Inhibitors such as the SphK1-selective inhibitor 1 (PF-543) 38, 39 and the SphK1/SphK2-dual inhibitor 5 (SKI-II) 40–42 have been co-crystallized with SphK1 and have been useful in developing next generation inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity

Childress¹,

Kharel

Brown³

et al. 2017

J. Med. Chem.

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Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors S1P1-5 to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this report, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK. Surprisingly, combining features of reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 Ki = 120 nM, hSphK2 Ki = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (Ki = 90 nM, 100-fold SphK2 selectivity). These compounds effectively decrease S1P levels in vitro. In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels.

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Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism

Cited by 16 publications

References 474 publications

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency

Sphingosine 1-Phosphate: A Novel Target for Lung Disorders

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity

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