Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

Bell, M. Elizabeth; Foley, David W.; Naylor, C.E.; Robinson, Colin; Riley, Jennifer; Epemolu, Ola; Scullion, Paul; Shishikura, Yoko; Katz, Elad; McLean, William; Wyatt, Paul G.; Read, Kevin D.; Woodland, Andrew

doi:10.1016/j.bmcl.2018.07.044

Cited by 18 publications

(14 citation statements)

References 25 publications

(26 reference statements)

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“…The biological responses to extracellular S1P are based on the regulation of S1P receptors (S1PRs) belonging to Gprotein coupled receptors 8 . Fingolimod and ponesimod are S1P receptor 1 (S1PR1) agonists, developed as immunomodulatory drugs to treat multiple sclerosis, psoriasis, and cancer 9 . Although previous findings indicate that sphingosine metabolites have great potential for cellular biological functions and therapeutic applications, their physicochemical nature and low yield cause their extraction and quantification to be challenging and expensive [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

et al. 2019

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O-cyclic phytosphingosine-1-phosphate (cP1P) is a novel chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate. Although structurally similar to sphingosine-1-phosphate (S1P), its biological properties in stem cells remain to be reported. We investigated the effect of cP1P on the therapeutic potential of mesenchymal stem cells (MSCs) and their regulatory mechanism. We found that, under hypoxia, cP1P suppressed MSC mitochondrial dysfunction and apoptosis. Metabolic data revealed that cP1P stimulated glycolysis via the upregulation of glycolysis-related genes. cP1P-induced hypoxia-inducible factor 1 alpha (HIF1α) plays a key role for MSC glycolytic reprogramming and transplantation efficacy. The intracellular calcium-dependent PKCα/mammalian target of the rapamycin (mTOR) signaling pathway triggered by cP1P regulated HIF1α translation via S6K1, which is critical for HIF1 activation. Furthermore, the cP1P-activated mTOR pathway induced bicaudal D homolog 1 expression, leading to HIF1α nuclear translocation. In conclusion, cP1P enhances the therapeutic potential of MSC through mTOR-dependent HIF1α translation and nuclear translocation.

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Section: Introductionmentioning

confidence: 99%

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

et al. 2019

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“…Ponesimod / ACT-128800, a selective modulator of S1PR1, S1PR4, and S1PR5 was evaluated in a phase 2 study (NST0128090), leading to a 75% reduction in area of involvement and severity index in 77% of patients [ 84 , 85 ]. The most frequent adverse events were dyspnea, elevated liver enzymes, headache, nasopharyngitis, dizziness, bradycardia, pruritus, and cough [ 85 ].…”

Section: S1pr Agonists/modulators In Immunological Disordersmentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Pérez-Jeldres

Álvarez-Lobos

Rivera–Nieves

2021

Drugs

110

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Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

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“…During the trial, dyspnea, increased liver enzyme concentrations, headache, nasopharyngitis, bradycardia, pruritus, and dizziness were observed [ 108 ]. However, the phase 3 clinical trial of ponesimod in psoriasis has not been started yet, possibly because severe side effects such as lymphopenia, bradycardia, and dyspnea were observed in other S1PR1 modulators [ 108 , 109 ].…”

Section: Treatmentmentioning

confidence: 99%

New Treatment Addressing the Pathogenesis of Psoriasis

Tokuyama

Mabuchi

2020

IJMS

173

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Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.

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Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

Abstract: Graphical abstract

Cited by 18 publications

References 25 publications

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

New Treatment Addressing the Pathogenesis of Psoriasis

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