Inhibition of Sphingosine 1-Phosphate Lyase for the Treatment of Rheumatoid Arthritis: Discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone Oxime (LX2931) and (1R,2S,3R)-1-(2-(Isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Bagdanoff, Jeffrey T.; Donoviel, Michael S.; Nouraldeen, Amr; Carlsen, Marianne; Jessop, Theodore C.; Tarver, James E.; Aleem, Saadat; Li, Dong; Zhang, Haiming; Boteju, Lakmal W.; Hazelwood, Jill; Yan, Jack; Bednarz, Mark S.; Layek, Suman; Owusu, Iris B.; Gopinathan, Suma; Moran, L; Lai, Zhong; Kramer, Jeff; Kimball, S. David; Yalamanchili, Padmaja; Heydorn, William E.; Frazier, Kenneth; Brooks, Barbara; Brown, Philip M.; Wilson, Alan G. E.; Sonnenburg, William K.; Main, Alan J.; Carson, Kenneth G.; Oravecz, Tamás; Augeri, David J.

doi:10.1021/jm101183p

Cited by 103 publications

(87 citation statements)

References 54 publications

(54 reference statements)

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“…6F), a candidate for the treatment of rheumatoid arthritis (Bagdanoff et al, 2010). As THI oxime is a derivative of THI we expected and found their beneficial effects to be similar in dystrophic muscles.…”

Section: Developmentmentioning

confidence: 93%

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Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

et al. 2013

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SUMMARYDuchenne muscular dystrophy is a lethal genetic disease characterized by the loss of muscle integrity and function over time. Using Drosophila, we show that dystrophic muscle phenotypes can be significantly suppressed by a reduction of wunen, a homolog of lipid phosphate phosphatase 3, which in higher animals can dephosphorylate a range of phospholipids. Our suppression analyses include assessing the localization of Projectin protein, a titin homolog, in sarcomeres as well as muscle morphology and functional movement assays. We hypothesize that wunen-based suppression is through the elevation of the bioactive lipid Sphingosine 1-phosphate (S1P), which promotes cell proliferation and differentiation in many tissues, including muscle. We confirm the role of S1P in suppression by genetically altering S1P levels via reduction of S1P lyase (Sply) and by upregulating the serine palmitoyl-CoA transferase catalytic subunit gene lace, the first gene in the de novo sphingolipid biosynthetic pathway and find that these manipulations also reduce muscle degeneration. Furthermore, we show that reduction of spinster (which encodes a major facilitator family transporter, homologs of which in higher animals have been shown to transport S1P) can also suppress dystrophic muscle degeneration. Finally, administration to adult flies of pharmacological agents reported to elevate S1P signaling significantly suppresses dystrophic muscle phenotypes. Our data suggest that localized intracellular S1P elevation promotes the suppression of muscle wasting in flies.

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Section: Developmentmentioning

confidence: 93%

“…6G). Finally, we tested FTY720, an analog of S1P and potent elevator of S1P signaling (Napoli, 2000;Bagdanoff et al, 2009;Bagdanoff et al, 2010), for its effect on muscle wasting when fed to Dys det1 /DysDf flies. Using…”

Section: Developmentmentioning

confidence: 99%

Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

et al. 2013

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“…Recent studies have implicated SPL as a potential immunomodulatory target in the context of autoimmune disease (41)(42)(43). LX2931, now in clinical trials for the treatment of rheumatoid arthritis, acts by inhibiting SPL and disrupting the S1P chemical gradient required for mature T-cell egress from the thymus and peripheral lymphoid organs and thereby preventing immune-mediated tissue damage ( 43 ).…”

Section: Whole Mount Survey Of Spl ␤ -Gal Reporter Expression In Adulmentioning

confidence: 99%

Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissues

Borowsky

Bandhuvula²,

Kumar³

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingosine-1-phosphate (S1P) is the fi nal metabolic product of sphingolipid degradation. It circulates in the blood and lymph bound to lipoproteins and functions as a ligand for a family of fi ve differentially expressed G proteincoupled receptors, the S1P receptors (S1PRs) ( 1, 2 ). Acting through these receptors and the downstream signaling events mediated by them, S1P infl uences cell migration, survival, and stress responses ( 3 ). S1PR signaling is critical for development, as demonstrated by the embryonic lethal phenotype of S1PR1 knockout mice, due to severe hemorrhage associated with impaired vascular maturation ( 4 ). S1PR2 knockout mice are deaf due to defects in the stria vascularis ( 5 ). Additional studies have demonstrated the importance of S1P transport and signaling in cardiac and brain development, reproduction, and embryonic stem cell survival ( 6-17 ). S1P acts through its cognate receptors to control T, B, natural killer, and hematopoietic stem cell traffi cking as these cells emerge from bone marrow and thymus and transit peripheral lymphoid organs ( 18,19 ). S1P signaling contributes to the regulation and constitutive activation of key transcription factors that play a central role in infl ammation and cancer, including nuclear factor-B and STAT3 ( 20,21 ). S1P is also a mediator of cardioprotection in response to ischemia and can reduce developmental cell death as well as apoptosis, tissue injury, and infertility in response to ionizing radiation ( 22-24 ). Although many effects of S1P signaling are mediated through activation of its receptors, some of its actions, including activation of nuclear factor-B signaling and regulation of histone deacetylases, appear to be mediated through the receptor-independent, intracellular functions of S1P ( 21,25 ). S1P is generated via phosphorylation of the sphingoid base sphingosine by sphingosine kinases SphK1 and SphK2Abstract Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in immunity, infl ammation, angiogenesis, and cancer. S1P lyase (SPL) is the essential enzyme responsible for S1P degradation. SPL augments apoptosis and is down-regulated in cancer. SPL generates a S1P chemical gradient that promotes lymphocyte traffi cking and as such is being targeted to treat autoimmune diseases. Despite growing interest in SPL as a disease marker, antioncogene, and pharmacological target, no comprehensive characterization of SPL expression in mammalian tissues has been reported. We investigated SPL expression in developing and adult mouse tissues by generating and characterizing a ␤ -galactosidase-SPL reporter mouse combined with immunohistochemistry, immunoblotting, and enzyme assays. SPL was expressed in thymic and splenic stromal cells, splenocytes, Peyer's Patches, colonic lymphoid aggregates, circulating T and B lymphocytes, granulocytes, and monocytes, with lowest expression in thymocytes. SPL was highly expressed within the CNS, including arachnoid lining cells, spinal cord, ch...

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“…In order to enhance S1P bioavailability, FTY720 or LX2931 administration was preferred to that of S1P itself since FTY720 has recently been FDA approved for use in multiple sclerosis and a phase 2A study has just been completed with promising results using LX2931 to treat rheumatoid arthritis. As such, these compounds, unlike synthetic S1P, have safety profiles in humans (24,45), which would make their application as malaria adjunctive therapy imminently testable, with possible accelerated translation to clinical populations.…”

Section: Genetic Approaches Using Hs1plmentioning

confidence: 99%

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney

Hawkes

Kain

et al. 2011

Mol Med

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Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL) -/-mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4 + and CD8 + T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

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Inhibition of Sphingosine 1-Phosphate Lyase for the Treatment of Rheumatoid Arthritis: Discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone Oxime (LX2931) and (1R,2S,3R)-1-(2-(Isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Cited by 103 publications

References 54 publications

Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissues

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

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