Abstract
The recent success of FTY720 (Fingolimod, Gilenya®), which has been approved for the treatment of relapsing–remitting multiple sclerosis and is the first-in-class sphingosine-1-phosphate (S1P) receptor modulating drug, has boosted the interest in further drug development in this area. Several selective S1P1 receptor-modulating drugs are being investigated in clinical trials for the treatment of diverse autoimmune disorders. Sphingosine kinase inhibitors are under development for the treatment of cancer, aberrant angiogenesis and inflammatory diseases; an inhibitor of SK2 with relatively low affinity is being analysed in patients with advanced solid tumours. While an indirect S1P lyase inhibitor has just failed the proof of concept in patients with rheumatoid arthritis, S1P lyase is still a promising target for the treatment of inflammatory and autoimmune diseases. Another approach is the development of S1P-scavenging or -clearing agents, including a monoclonal S1P antibody that has successfully passed phase I clinical trials and will be further developed for age-related macular degeneration.
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References
Antoon JW, White MD, Meacham WD, Slaughter EM, Muir SE, Elliott S, Rhodes LV, Ashe HB, Wiese TE, Smith CD, Burow ME, Beckman BS (2010) Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology 151:5124–5135
Bagdanoff JT et al (2009) Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders. J Med Chem 52:3941–3953
Bagdanoff JT et al (2010) 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). J Med Chem 53:8650–8662
Beljanski V, Knaak C, Zhuang Y, Smith CD (2011a) Combined anticancer effects of sphingosine kinase inhibitors and sorafenib. Invest New Drugs 29:1132–1142
Beljanski V, Lewis CS, Smith CD (2011b) Antitumor activity of sphingosine kinase-2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther 11:524–534
Blé F, Cannet C, Zurbruegg S, Gérard C, Frossard N, Beckmann N, Trifilieff A (2009) Activation of the lung S1P1 receptor reduces allergen-induced plasma leakage in mice. Br J Pharmacol 158:1295–1301
Bolli MH et al (2010) 2-Imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem 53:4198–4211
Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9:883–897
Caballero S, Swaney J, Moreno K, Afzal A, Kielczewski J, Stoller G, Cavalli A, Garland W, Hansen G, Sabbadini R, Grant MB (2009) Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization. Exp Eye Res 88:367–377
Chi H (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci 32:16–24
Choi JW, Gardell SE, Herr DR, Rivera R, Lee C, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor-1 (S1P1) modulation. Proc Natl Acad Sci U S A 108:751–756
Chumanevich AA, Poudyal D, Cui X, Davis T, Wood PA, Smith CD, Hofseth LJ (2010) Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis 31:1787–1793
Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH (2010) International Union of Basic and Clinical Pharmacology LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev 62:579–587
Cohen JA, Barkhof F, Comi G, Hartung H, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362:402–415
Cohen JA, Chun J (2011) Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 69:759–777
David OJ, Kovarik JM, Schmouder RL (2012) Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet 51:15–28
Edmonds Y, Milstien S, Spiegel S (2011) Development of small-molecule inhibitors of sphingosine-1-phosphate signaling. Pharmacol Ther 132:352–360
Espinosa PS, Berger JR (2011) Delayed fingolimod-associated asystole. Mult Scler 17:1387–1389
Fitzpatrick LR, Green C, Frauenhoffer EE, French KJ, Zhuang Y, Maines LW, Upson JJ, Paul E, Donahue H, Mosher TJ, Smith CD (2011a) Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase. Inflammopharmacology 19:75–87
Fitzpatrick LR, Green C, Maines LW, Smith CD (2011b) Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2. Pharmacology 87:135–143
French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, Yun JK, Smith CD (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63:5962–5969
French KJ, Upson JJ, Keller SN, Zhuang Y, Yun JK, Smith CD (2006) Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther 318:596–603
French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD (2010) Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther 333:129–139
Fujii Y, Hirayama T, Ohtake H, Ono N, Inoue T, Sakurai T, Takayama T, Matsumoto K, Tsukahara N, Hidano S, Harima N, Nakazawa K, Igarashi Y, Goitsuka R (2012) Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities. J Immunol 188:206–215
Fukuhara S, Simmons S, Kawamura S, Inoue A, Orba Y, Tokudome T, Sunden Y, Arai Y, Moriwaki K, Ishida J, Uemura A, Kiyonari H, Abe T, Fukamizu A, Hirashima M, Sawa H, Aoki J, Ishii M, Mochizuki N (2012) The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. J Clin Invest 122:416–1426
Gergely P, Wallstroem E, Nuesslein-Hildesheim B, Bruns C, Zecri F, Cooke N, Traebert M, Tuntland T, Rosenberg M, Saltzman M (2009) Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans. Mult Scler 15:S125–S126, Abstract
Gonzalez-Cabrera PJ, Cahalan SM, Nguyen N, Sarkisyan G, Leaf NB, Cameron MD, Kago T, Rosen H (2012) S1P1 receptor modulation with cyclical recovery from lymphopenia ameliorates mouse model of multiple sclerosis. Mol Pharmacol 81:166–174
Gonzalez-Cabrera PJ, Jo E, Sanna MG, Brown S, Leaf N, Marsolais D, Schaeffer M, Chapman J, Cameron M, Guerrero M, Roberts E, Rosen H (2008) Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. Mol Pharmacol 74:1308–1318
Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150
Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335:851–855
Hla T, Venkataraman K, Michaud J (2008) The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta 1781:477–482
Huwiler A, Bourquin F, Kotelevets N, Pastukhov O, Capitani G, Grütter MG, Zangemeister-Wittke U (2011) A prokaryotic S1P lyase degrades extracellular S1P in vitro and in vivo: implication for treating hyperproliferative disorders. PLoS One 6:e22436
Huwiler A, Pfeilschifter J (2008) New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets. Biochem Pharmacol 75:1893–1900
Igarashi N, Okada T, Hayashi S, Fujita T, Jahangeer S, Nakamura S (2003) Sphingosine kinase-2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem 278:46832–46839
Jackson SJ, Giovannoni G, Baker D (2011) Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation 8:76
Kapitonov D, Allegood JC, Mitchell C, Hait NC, Almenara JA, Adams JK, Zipkin RE, Dent P, Kordula T, Milstien S, Spiegel S (2009) Targeting sphingosine kinase-1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res 69:6915–6923
Kappos L, Radue E, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401
Kennedy AJ, Mathews TP, Kharel Y, Field SD, Moyer ML, East JE, Houck JD, Lynch KR, Macdonald TL (2011) Development of amidine-based sphingosine kinase-1 nanomolar inhibitors and reduction of sphingosine-1-phosphate in human leukemia cells. J Med Chem 54:3524–3548
Kharel Y, Mathews TP, Gellett AM, Tomsig JL, Kennedy PC, Moyer ML, Macdonald TL, Lynch KR (2011) Sphingosine kinase type-1 inhibition reveals rapid turnover of circulating sphingosine-1-phosphate. Biochem J 440:345–353
Killestein J, Rudick RA, Polman CH (2011) Oral treatment for multiple sclerosis. Lancet Neurol 10:1026–1034
Kumar A, Saba JD (2009) Lyase to live by: sphingosine phosphate lyase as a therapeutic target. Expert Opin Ther Targets 13:1013–1025
Lai W, Irwan AW, Goh HH, Melendez AJ, McInnes IB, Leung BP (2009) Distinct roles of sphingosine kinase-1 and -2 in murine collagen-induced arthritis. J Immunol 183:2097–2103
Lim KG, Sun C, Bittman R, Pyne NJ, Pyne S (2011) (R)-FTY720 methyl ether is a specific sphingosine kinase-2 inhibitor: effect on sphingosine kinase-2 expression in HEK-293 cells and actin rearrangement and survival of MCF-7 breast cancer cells. Cell Signal 23:1590–1595
Liu H, Toman RE, Goparaju SK, Maceyka M, Nava VE, Sankala H, Payne SG, Bektas M, Ishii I, Chun J, Milstien S, Spiegel S (2003) Sphingosine kinase type-2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 278:40330–40336
Loveridge C, Tonelli F, Leclercq T, Lim KG, Long JS, Berdyshev E, Tate RJ, Natarajan V, Pitson SM, Pyne NJ, Pyne S (2010) The sphingosine kinase-1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase-1 in mammalian cells. J Biol Chem 285:38841–38852
Maceyka M, Harikumar KB, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22:50–60
Maines LW, Fitzpatrick LR, French KJ, Zhuang Y, Xia Z, Keller SN, Upson JJ, Smith CD (2008) Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 53:997–1012
Maines LW, Fitzpatrick LR, Green CL, Zhuang Y, Smith CD (2010) Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacology 18:73–85
Moberly JB, Rohatagi S, Zahir H, Hsu C, Noveck RJ, Truitt KE (2012) Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine-1-phosphate receptor-1 modulator. J Clin Pharmacol 52:996–1006
Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K (2009) Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 5:428–434
O’Brien N, Jones ST, Williams DG, Cunningham HB, Moreno K, Visentin B, Gentile A, Vekich J, Shestowsky W, Hiraiwa M, Matteo R, Cavalli A, Grotjahn D, Grant M, Hansen G, Campbell M, Sabbadini R (2009) Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies. J Lipid Res 50:2245–2257
Oo ML, Thangada S, Wu M, Liu CH, Macdonald TL, Lynch KR, Lin C, Hla T (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 282:9082–9089
Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S, Liu Y, Gao W, Chu A, Brinkmann V, Bruns C, Streiff M, Cannet C, Cooke N, Gray N (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol 13:1227–1234
Parrill AL, Wang D, Bautista DL, van Brocklyn JR, Lorincz Z, Fischer DJ, Baker DL, Liliom K, Spiegel S, Tigyi G (2000) Identification of Edg1 receptor residues that recognize sphingosine-1-phosphate. J Biol Chem 275:39379–39384
Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T, Milstien S, Adams JK, Zipkin RE, Grant S, Spiegel S (2008) A selective sphingosine kinase-1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood 112:1382–1391
Pelletier D, Hafler DA (2012) Fingolimod for multiple sclerosis. N Engl J Med 366:339–347
Piali L, Froidevaux S, Hess P, Nayler O, Bolli MH, Schlosser E, Kohl C, Steiner B, Clozel M (2011) The selective sphingosine 1-phosphate receptor-1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther 337:547–556
Pitson SM (2011) Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci 36:97–107
Pyne NJ, Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10:489–503
Ren S, Xin C, Pfeilschifter J, Huwiler A (2010) A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): induction of lysosomal sphingosine kinase-1 degradation. Cell Physiol Biochem 26:97–104
Sabbadini RA (2011) Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration. Br J Pharmacol 162:1225–1238
Sanna MG, Liao J, Jo E, Alfonso C, Ahn M, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279:13839–13848
Sanna MG, Wang S, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, Wei SH, Parker I, Jo E, Cheng W, Cahalan MD, Wong C, Rosen H (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2:434–441
Schmahl J, Raymond CS, Soriano P (2007) PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39:52–60
Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309:1735–1739
Shea BS, Brooks SF, Fontaine BA, Chun J, Luster AD, Tager AM (2010) Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury. Am J Respir Cell Mol Biol 43:662–673
Snider AJ, Orr Gandy KA, Obeid LM (2010) Sphingosine kinase: role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 92:707–715
Song J, Matsuda C, Kai Y, Nishida T, Nakajima K, Mizushima T, Kinoshita M, Yasue T, Sawa Y, Ito T (2008) A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice. J Pharmacol Exp Ther 324:276–283
Tarrasón G, Aulí M, Mustafa S, Dolgachev V, Domènech MT, Prats N, Domínguez M, López R, Aguilar N, Calbet M, Pont M, Milligan G, Kunkel SL, Godessart N (2011) The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice. Int Immunopharmacol 11:1773–1779
Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG, Garland WA, Lu Y, Yu S, Hall HS, Kundra V, Mills GB, Sabbadini RA (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9:225–238
Vogel P, Donoviel MS, Read R, Hansen GM, Hazlewood J, Anderson SJ, Sun W, Swaffield J, Oravecz T (2009) Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PLoS One 4:e4112
Wenderfer SE, Stepkowski SM, Braun MC (2008) Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. Kidney Int 74:1319–1326
Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA (2009) Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 218:192–198
Yonesu K, Kubota K, Tamura M, Inaba S, Honda T, Yahara C, Watanabe N, Matsuoka T, Nara F (2011) Purification and identification of activating enzymes of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator, in erythrocytes. J Biol Chem 286:24765–24775
Zhang Z, Zhang Z, Zug C, Nuesslein-Hildesheim B, Leppert D, Schluesener HJ (2009) AUY954, a selective S1P1 modulator, prevents experimental autoimmune neuritis. J Neuroimmunol 216:59–65
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zu Heringdorf, D.M., Ihlefeld, K., Pfeilschifter, J. (2013). Pharmacology of the Sphingosine-1-Phosphate Signalling System. In: Gulbins, E., Petrache, I. (eds) Sphingolipids: Basic Science and Drug Development. Handbook of Experimental Pharmacology, vol 215. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1368-4_13
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